FcRn Antibodies and Methods of Use Thereof

ABSTRACT

The present invention features antibodies that have high binding affinity to human neonatal Fc receptor (FcRn). These anti-FcRn antibodies are useful, e.g., to promote clearance of autoantibodies in a subject, to suppress antigen presentation in a subject, to block an immune response, e.g., block an immune complex-based activation of the immune response in a subject, and to treat immunological diseases (e.g., autoimmune diseases) in a subject.

BACKGROUND OF THE INVENTION

Therapeutic proteins, e.g., therapeutic antibodies, have rapidly becomea clinically important drug class for patients with immunologicaldiseases.

SUMMARY OF THE INVENTION

The present invention features novel antibodies to human neonatal Fcreceptor (FcRn). These anti-FcRn antibodies are useful, e.g., to promoteclearance of autoantibodies in a subject, to suppress antigenpresentation in a subject, to block an immune response, e.g., block animmune complex-based activation of the immune response in a subject, orto treat immunological diseases (e.g., autoimmune diseases) in asubject.

In one aspect, the invention features an isolated antibody that binds tohuman FcRn. The isolated antibody contains: (1) a light chain variableregion that includes a CDR L1, a CDR L2, and a CDR L3 and (2) a heavychain variable region that includes a CDR H1, a CDR H2, and a CDR H3,wherein the CDR L1 has a sequence having no more than two amino acidsubstitutions relative to the sequence of TGTGSDVGSYNLVS (SEQ ID NO: 1),the CDR L2 has a sequence having no more than one amino acidsubstitutions relative to the sequence of GDSERPS (SEQ ID NO: 2), theCDR L3 has a sequence having no more than one amino acid substitutionsrelative to the sequence of SSYAGSGIYV (SEQ ID NO: 3), the CDR H1 has asequence having no more than one amino acid substitutions relative tothe sequence of TYAMG (SEQ ID NO: 4), DYAMG (SEQ ID NO: 5), or NYAMG(SEQ ID NO: 6), the CDR H2 has a sequence having no more than two aminoacid substitutions relative to the sequence of SIGSSGAQTRYADS (SEQ IDNO: 7), SIGASGSQTRYADS (SEQ ID NO: 8), SIGASGAQTRYADS (SEQ ID NO: 9), orSIGASGGOTRYADS (SEQ ID NO: 10), and the CDR H3 has a sequence having nomore than one amino acid substitutions relative to the sequence ofLAIGDSY (SEQ ID NO: 11).

In some embodiments, the antibody binds human FcRn with a K_(D) of lessthan 200, 150, 100, 50, or 40 pM.

In some embodiments, the antibody binds human FcRn with a K_(D) that isless than or equal to that of an antibody having the light chainvariable region and heavy chain variable region of N022, N023, N024,N026, or N027, and further having the same Fc region as that of theantibody to which it is being compared.

In another aspect, the invention features an isolated antibodycontaining: (1) a light chain variable region that includes a CDR L1, aCDR L2, and a CDR L3 and (2) a heavy chain variable region that includesa CDR H1, a CDR H2, and a CDR H3, wherein the CDR L1 has the sequence ofX₁GTGSDVGSYNX₂VS (SEQ ID NO: 12), the CDR L2 has the sequence ofGDX₃X₄RPS (SEQ ID NO: 13), the CDR L3 has the sequence of X₅SYX₆GSGIYV(SEQ ID NO: 14), the CDR H1 has the sequence of Z₁YAMG (SEQ ID NO: 15),the CDR H2 has the sequence of SIGZ₂SGZ₃QTZ₄YADS (SEQ ID NO: 16), andthe CDR H3 has the sequence of LAZ₅Z₆DSY (SEQ ID NO: 17), wherein X₁ isa polar or hydrophobic amino acid, X₂ is a hydrophobic amino acid, X₃ isa polar amino acid, X₄ is a polar or acidic amino acid, X₅ is a polar orhydrophobic amino acid, X₆ is a hydrophobic amino acid, Z₁ is a polar oracidic amino acid, Z₂ is a polar or hydrophobic amino acid, Z₃ is G, S,or A, Z₄ is a basic amino acid, Z₅ is a hydrophobic or basic amino acid,and Z₆ is G, S, D, Q, or H, and wherein the antibody binds human FcRnwith a K_(D) that is less than or equal to that of antibody having thelight chain variable region and heavy chain variable region of N026 andfurther having the same Fc region as the antibody being compared. Insome embodiments, X₁ is T, A, S, or I. In other embodiments, X₂ is L orI. In some embodiments, X₃ is S, N, or T. In still other embodiments, X₄is Q, E, or N, X₅ is C, S, I, or Y. In some embodiments, X₆ is A or V,Z₁ is E, T, D, or N. In further embodiments, Z₂ is S or A. In someembodiments, Z₄ is K or R. In yet other embodiments, Z₅ is I, L or H.

In another aspect, the invention features an isolated antibodycontaining a light chain variable region that includes a CDR L1 havingthe sequence of TGTGSDVGSYNLVS (SEQ ID NO: 1), a CDR L2 having thesequence of GDSERPS (SEQ ID NO: 2), and a CDR L3 having the sequence ofSSYAGSGIYV (SEQ ID NO: 3), and a heavy chain variable region thatincludes a CDR H1 having the sequence of Z₁YAMG (SEQ ID NO: 15), a CDRH2 having the sequence of SIGZ₂SGZ₃QTRYADS (SEQ ID NO: 18), and a CDR H3having the sequence of LAIGDSY (SEQ ID NO: 11), wherein Z₁ is T, D, orN, Z₂ is S or A, and Z₃ is G, S or A.

In some embodiments, the isolated antibody contains a CDR L1 having thesequence of TGTGSDVGSYNLVS (SEQ ID NO: 1), a CDR L2 having the sequenceof GDSERPS (SEQ ID NO: 2), a CDR L3 having the sequence of SSYAGSGIYV(SEQ ID NO: 3), a CDR H1 having the sequence of TYAMG (SEQ ID NO: 4), aCDR H2 having the sequence of SIGSSGAQTRYADS (SEQ ID NO: 7), and a CDRH3 having the sequence of LAIGDSY (SEQ ID NO: 11).

In some embodiments, the isolated antibody contains a CDR L1 having thesequence of TGTGSDVGSYNLVS (SEQ ID NO: 1), a CDR L2 having the sequenceof GDSERPS (SEQ ID NO: 2), a CDR L3 having the sequence of SSYAGSGIYV(SEQ ID NO: 3), a CDR H1 having the sequence of DYAMG (SEQ ID NO: 5), aCDR H2 having the sequence of SIGASGSQTRYADS (SEQ ID NO: 8), and a CDRH3 having the sequence of LAIGDSY (SEQ ID NO: 11).

In some embodiments, the isolated antibody contains a CDR L1 having thesequence of TGTGSDVGSYNLVS (SEQ ID NO: 1), a CDR L2 having the sequenceof GDSERPS (SEQ ID NO: 2), a CDR L3 having the sequence of SSYAGSGIYV(SEQ ID NO: 3), a CDR H1 having the sequence of NYAMG (SEQ ID NO: 6), aCDR H2 having the sequence of SIGASGAQTRYADS (SEQ ID NO: 9), and a CDRH3 having the sequence of LAIGDSY (SEQ ID NO: 11).

In other embodiments, the isolated antibody contains a CDR L1 having thesequence of TGTGSDVGSYNLVS (SEQ ID NO: 1), a CDR L2 having the sequenceof GDSERPS (SEQ ID NO: 2), a CDR L3 having the sequence of SSYAGSGIYV(SEQ ID NO: 3), a CDR H1 having the sequence of TYAMG (SEQ ID NO: 4), aCDR H2 having the sequence of SIGASGGQTRYADS (SEQ ID NO: 10), and a CDRH3 having the sequence of LAIGDSY (SEQ ID NO: 11).

In yet other embodiments, the isolated antibody contains a CDR L1 havingthe sequence of TGTGSDVGSYNLVS (SEQ ID NO: 1), a CDR L2 having thesequence of GDSERPS (SEQ ID NO: 2), a CDR L3 having the sequence ofSSYAGSGIYV (SEQ ID NO: 3), a CDR H1 having the sequence of TYAMG (SEQ IDNO: 4), a CDR H2 having the sequence of SIGASGSQTRYADS (SEQ ID NO: 8),and a CDR H3 having the sequence of LAIGDSY (SEQ ID NO: 11).

In some embodiments, the light chain variable region of the isolatedantibody of the invention has a sequence having at least 90% identity tothe sequence of

(SEQ) ID NO: 19) QSALTQPASVSGSPGQSITISCTGTGSDVGSYNLVSWYQQHPGKAPKLMIYGDSERPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYAGSGIYVFGTGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHKSYS CQVTHEGSTVEKTVAPTECS.

In some embodiments, the heavy chain variable region of the isolatedantibody of the invention has a sequence having at least 90% identity tothe sequence of

(SEQ ID NO: 20) EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMGWVRQAPGKGLEWVSSIGSSGAQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPFKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLICLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS LSPG.

In other embodiments, the heavy chain variable region of the isolatedantibody of the invention has a sequence having at least 90% identity tothe sequence of

(SEQ ID NO: 21) EVQLLESGGGLVQPGGSLRLSCAASGFTFSDYAMGWVRQAPGKGLEWVSSIGASGSQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNFIKPSNTKVDKKVEPKSCDKTFITCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS LSLSPG.

In other embodiments, the heavy chain variable region of the isolatedantibody of the invention has a sequence having at least 90% identity tothe sequence of

(SEQ ID NO: 22) EVQLLESGGGLVQPGGSLRLSGAASGFTFSNYAMGWVRQAPGKGLEWVSSIGASGAQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYGARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTFITCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTGLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSGSVMHEALHNHYTQKSL SLSPG.

In some embodiments, the heavy chain variable region of the isolatedantibody of the invention has a sequence having at least 90% identity tothe sequence of

(SEQ ID NO: 23) EVQLLESGGGLVQPGGSLRLSGAASGFTFSTYAMGWVRQAPGKGLEWVSSIGASGGQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYGARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGGLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSGDKTHTGPPGPAPELLGGPSVFLFPPKPKDTLMISRTPEVTGVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLFIQDWLNGKEYKGKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTGLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSGSVMHEAL HNHYTQKSLSLSPG.

In other embodiments, the heavy chain variable region of the isolatedantibody of the invention has a sequence having at least 90% identity tothe sequence of

(SEQ ID NO: 24) EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMGWVRQAPGKGLEWVSSIGASGSQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFIDEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL HNHYTQKSLSLSPG.

In another aspect, the invention features an isolated antibodycontaining a light chain variable region and a heavy chain variableregion, wherein the light chain variable region has a sequence having atleast 90% identity to the sequence of

(SEQ ID NO: 19) QSALTQPASVSGSPGQSITISCTGTGSDVGSYNLVSWYQQHPGKAPKLMIYGDSERPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYAGSGIYVFGTGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHKSYSCQVTHEGS TVEKTVAPTECS;and the heavy chain variable region has a sequence having at least 90%identity to the sequence of

(SEQ ID NO: 20) EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMGWVRQAPGKGLEWVSSIGSSGAQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVIVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPG.

In another aspect, the invention features an isolated antibodycontaining a light chain variable region and a heavy chain variableregion, wherein the light chain variable region has a sequence having atleast 90% identity to the sequence of

(SEQ ID NO: 19) QSALTQPASVSGSPGQSITISCTGTGSDVGSYNLVSWYQQHPGKAPKLMIYGDSERPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYAGSGIYVFGTGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHKSYSCQVTHEGS TVEKTVAPTECS;and the heavy chain variable region has a sequence having at least 90%identity to the sequence of

(SEQ ID NO: 21) EVQLLESGGGLVQPGGSLRLSCAASGFTFSDYAMGWVRQAPGKGLEWVSSIGASGSQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVIVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNFIKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPG.

In another aspect, the invention features an isolated antibodycontaining a light chain variable region and a heavy chain variableregion, wherein the light chain variable region has a sequence having atleast 90% identity to the sequence of

(SEQ ID NO: 19) QSALTQPASVSGSPGQSITISCTGTGSDVGSYNLVSWYQQHPGKAPKLMIYGDSERPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYAGSGIYVFGTGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHKSYSCQVTHEGS TVEKTVAPTECS;and the heavy chain variable region has a sequence having at least 90%identity to the sequence of

(SEQ ID NO: 22) EVQLLESGGGLVQPGGSLRLSCAASGFTFSNYAMGWVRQAPGKGLEWVSSIGASGAQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPG.

In another aspect, the invention features an isolated antibodycontaining a light chain variable region and a heavy chain variableregion, wherein the light chain variable region has a sequence having atleast 90% identity to the sequence of

(SEQ ID NO: 19) QSALTQPASVSGSPGQSITISCTGTGSDVGSYNLVSWYQQHPGKAPKLMIYGDSERPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYAGSGIYVFGTGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHKSYSCQVTHEGS TVEKTVAPTECS;and the heavy chain variable region has a sequence having at least 90%identity to the sequence of

(SEQ ID NO: 23) EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMGWVRQAPGKGLEWVSSIGASGGQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVUDSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPG.

In yet another aspect, the invention features an isolated antibodycontaining a light chain variable region and a heavy chain variableregion, wherein the light chain variable region has a sequence having atleast 90% identity to the sequence of

(SEQ ID NO: 19) QSALTQPASVSGSPGQSITISCTGTGSDVGSYNLVSWYQQHPGKAPKLMIYGDSERPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYAGSGIYVFGTGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHKSYSCQVTHEGS TVEKTVAPTECS;and the heavy chain variable region has a sequence having at least 90%identity to the sequence of

(SEQ ID NO: 24) EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMGVVVRQAPGKGLEWVSSIGASGSQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYVVGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA LHNHYTQKSLSLSPG.

In some embodiments, the heavy chain variable region of the isolatedantibody of the invention has a sequence having at least 95%, 97%, 99%,or 100% identity to the sequence of any one of SEQ ID NOs: 20-24. Inother embodiments, the light chain variable region of the isolatedantibody of the invention has a sequence having at least 95%, 97%, 99%,or 100% identity to the sequence of SEQ ID NO: 19.

In some embodiments, the isolated antibody of the invention furtherincludes amino acid substitution N297A, relative to the sequence of anyone of SEQ ID NOs: 20-24.

In other embodiments, the isolated antibody further includes amino acidsubstitutions D355E and L357M, relative to the sequence of any one ofSEQ ID NOs: 20-24.

In other embodiments, the isolated antibody of the invention furtherincludes any one or more of the following amino acid substitutions:A23V, S30R, L80V, A84T, E85D, A93V, relative to the sequence of any oneof SEQ ID NOs: 20-24 and Q38H, V58I, and G99D, relative to the sequenceof SEQ ID NO: 19.

In yet other embodiment, the isolated antibody of the invention does notcontain a C-terminal lysine at residue 446, relative to the sequence ofany one of SEQ ID NOs: 20-24.

In some embodiments, the antibody of any of the above aspects bindshuman FcRn with a K_(D) that is less than or equal to that of anantibody having the light chain variable region and heavy chain variableregion of N022, N023, N024, N026, or N027 and also having the same Fcregion as that of the antibody being compared. For example, in aparticular K_(D) assay, the K_(D) of the antibody is less than 200, 150,100, 50, or 40 pM.

The amino acid positions assigned to complementary determining regions(CDRs) and framework regions (FRs) of any isolated antibody describedherein are defined according to EU index of Kabat (Sequences of Proteinsof Immunological Interest, 5th Ed. Public Health Service, NationalInstitutes of Health, Bethesda, Md. (1991)).

In another aspect, the invention features an isolated antibodycontaining a light chain variable region and a heavy chain variableregion, wherein the light chain variable region has the sequence of

(SEQ ID NO: 19) QSALTQPASVSGSPGQSITISCTGTGSDVGSYNLVSWYQQHPGKAPKLMIYGDSERPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYAGSGIYVFGTGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHKSYSCQVTHEGS TVEKTVAPTECS;and the heavy chain variable region has the sequence of

(SEQ ID NO: 20) EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMGWVRQAPGKGLEWVSSIGSSGAQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFIDEPVINSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNFIKPSNTKVDKKVEPKSCDKTFITCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEMISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDQSFFLYSKLTVDKSRWQQGNVFSCSVMHEA LHNHYTQKSLSLSPG.

In another aspect, the invention features an isolated antibodycontaining a light chain variable region and a heavy chain variableregion, wherein the light chain variable region has the sequence of

(SEQ ID NO: 19) QSALTQPASVSGSPGQSITISCTGTGSDVGSYNLVSWYQQHPGKAPKLMIYGDSERPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYAGSGIYVFGTGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHKSYSCQVTHEGS TVEKTVAPTECS;and the heavy chain variable region has the sequence of

(SEQ ID NO: 21) EVQLLESGGGLVQPGGSLRLSCAASGFTFSDYAMGWVRQAPGKGLEWVSSIGASGSQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVIVSWNSGALTSGVFITFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNFIKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLFIQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPG.

In another aspect, the invention features an isolated antibodycontaining a light chain variable region and a heavy chain variableregion, wherein the light chain variable region has the sequence of

(SEQ ID NO: 19) QSALTQPASVSGSPGQSITISCTGTGSDVGSYNLVSWYQQHPGKAPKLMIYGDSERPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYAGSGIYVFGTGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHKSYSCQVTHEGS TVEKTVAPTECS;and the heavy chain variable region has the sequence of

(SEQ ID NO: 22) EVQLLESGGGLVQPGGSLRLSCAASGFTFSNYAMGWVRQAPGKGLEWVSSIGASGAQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPG.

In another aspect, the invention features an isolated antibodycontaining a light chain variable region and a heavy chain variableregion, wherein the light chain variable region has the sequence of

(SEQ ID NO: 19) QSALTQPASVSGSPGQSITISCTGTGSDVGSYNLVSWYQQHPGKAPKLMIYGDSERPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYAGSGIYVFGTGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHKSYSCQVTHEGS TVEKTVAPTECS;and the heavy chain variable region has the sequence of

(SEQ ID NO: 23) EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMGWVRQAPGKGLEWVSSIGASGGQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG.

In yet another aspect, the invention features an isolated antibodycontaining a light chain variable region and a heavy chain variableregion, wherein the light chain variable region has the sequence of

(SEQ ID NO: 19) QSALTQPASVSGSPGQSITISCTGTGSDVGSYNLVSWYQQHPGKAPKLMIYGDSERPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYAGSGIYVFGTGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHKSYSCQVTHEGS TVEKTVAPTECS;and the heavy chain variable region has the sequence of

(SEQ ID NO: 24) EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMGWVRQAPGKGLEWVSSIGASGSQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG.

In some embodiments of any of the above aspects, the isolated antibodyof the invention is a monoclonal antibody. In some embodiments, theisolated antibody is IgG1. In some embodiments, the isolated antibodyincludes a λ light chain. In some embodiments, the isolated antibodyincludes a kappa light chain. In some embodiments, the glycosylationsite on the Fc region of the isolated antibody is sialylated (e.g.,disialylated).

In some embodiments of any of the above aspects, the isolated antibodyof the invention is a humanized or fully human antibody.

In some embodiments, the isolated antibody binds to human FcRn with aK_(D) of 1-100, 5-150, 5-100, 5-75, 5-50, 10-50, or 10-40 pM.

In some embodiments, the isolated antibody of the invention bindsrodent, e.g., mouse or rat FcRn. In some embodiments, the isolatedantibody of the invention binds rodent, e.g., mouse or rat, FcRn with aK_(D) of less than 200, 150, 100, 50, or 40 pM.

In another aspect, the invention features a nucleic acid moleculeencoding any isolated antibody described herein.

In yet another aspect, the invention features a vector containing anucleic acid molecule encoding any antibody described herein.

In another aspect, the invention features a host cell that expresses anyisolated antibody described herein. The host cell includes a nucleicacid molecule encoding any isolated antibody described herein or avector containing a nucleic acid molecule encoding any isolated antibodydescribed herein, wherein the nucleic acid molecule or vector isexpressed by the host cell.

In some embodiments, the host cell is a Chinese hamster ovary (CHO)cell. In some embodiment, the host cell is an Sp2 cell or NS0 cell.

In another aspect, the invention features a method of preparing anyisolated antibody described herein. The method includes: a) providing ahost cell that includes a nucleic acid molecule encoding any isolatedantibody described herein or a vector containing a nucleic acid moleculeencoding any isolated antibody described herein, and b) expressing thenucleic acid molecule or vector in the host cell under conditions thatallow for the formation of the antibody.

In some embodiments, the method includes the step of recovering theantibody from the host cell. e.g., at a concentration of about 1-100,1-50, 1-25, 2-50, 5-50, or 2-20 mg/ml.

In other embodiments, the host cell used in the method is a CHO cell.

In another aspect, the invention features a pharmaceutical compositionincluding any isolated antibody described herein and one or morepharmaceutically acceptable carriers or excipients.

In some embodiments, the pharmaceutical composition includes theantibody in a therapeutically effective dose amount.

In another aspect, the invention features a method of increasing IgGcatabolism in a subject. In another aspect, the invention features amethod of reducing autoantibodies in a subject. In yet another aspect,the invention features a method of treating or reducing an immunecomplex-based activation of an immune response in a subject. The methodsinclude administering to the subject any isolated antibody describedherein or a pharmaceutical composition including any isolated antibodydescribed herein.

In some embodiments, the immune response in the subject is an acute orchronic immune response.

In some embodiments, the subject has or the acute immune response isactivated by a medical condition selected from the group consisting ofpemphigus vulgaris, lupus nephritis, myasthenia gravis, Guillain-Barrésyndrome, antibody-mediated rejection, catastrophic anti-phospholipidantibody syndrome, immune complex-mediated vasculitis, glomerulitis, achannelopathy, neuromyelitis optica, autoimmune hearing loss, idiopathicthrombocytopenia purpura (ITP), autoimmune haemolytic anaemia (AIHA),immune neutropenia, dilated cardiomyopathy, and serum sickness.

In some embodiments, the subject has or the chronic immune response isactivated by a medical condition selected from the group consisting ofchronic inflammatory demyelinating polyneuropathy (CIDP), systemiclupus, a chronic form of a disorder indicated for acute treatment,reactive arthropathies, primary biliary cirrhosis, ulcerative colitis,and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis.

In some embodiments, the subject has or the immune response is activatedby an autoimmune disease. In particular, the autoimmune disease isselected from the group consisting of alopecia areata, ankylosingspondylitis, antiphospholipid syndrome, Addison's disease, hemolyticanemia, autoimmune hepatitis, hepatitis, Behcet's disease, bullouspemphigoid, cardiomyopathy, celiac sprue-dermatitis, chronic fatigueimmune dysfunction syndrome, chronic inflammatory demyelinatingpolyneuropathy, Churg-Strauss syndrome, cicatricial pemphigoid, limitedscleroderma (CREST syndrome), cold agglutinin disease, Crohn's disease,dermatomyositis, discoid lupus, essential mixed cryoglobulinemia,fibromyalgia, fibromyositis, Graves' disease, Hashimoto's thyroiditis,hypothyroidism, inflammatory bowel disease, autoimmunelymphoproliferative syndrome, idiopathic pulmonary fibrosis, IgAnephropathy, insulin dependent diabetes, juvenile arthritis, lichenplanus, lupus, Ménière's Disease, mixed connective tissue disease,multiple sclerosis, pernicious anemia, polyarteritis nodosa,polychondritis, polyglandular syndromes, polymyalgia rheumatica,polymyositis, primary agammaglobulinemia, primary biliary cirrhosis,psoriasis, Raynaud's phenomenon, Reiter's syndrome, rheumatic fever,rheumatoid arthritis, sarcoidosis, scleroderma, Sjögren's syndrome,stiff-man syndrome, Takayasu arteritis, temporal arteritis, ulcerativecolitis, uveitis, vitiligo, and Wegener's granulomatosis.

Definitions

The term “antibody” herein is used in the broadest sense and encompassesvarious antibody structures, including but not limited to monocionalantibodies, polyclonal antibodies, multispecific antibodies (e.g.,bispecific antibodies), and antibody fragments so long as they exhibitFcRn antigen-binding activity.

“Antibody fragments” comprise a portion of an intact antibody,preferably the antigen binding or variable region of the intactantibody. Examples of antibody fragments include Fab, Fab′, F(ab′)₂, andFv fragments, diabodies, linear antibodies, single-chain antibodymolecules, and multispecific antibodies.

As used herein, the term “isolated antibody” refers to an antibody whichhas been separated and/or recovered from a component of itsmanufacturing host cell environment. Contaminant components of itsmanufacturing host cell environment are materials which would interferewith research, diagnostic, or therapeutic uses of the antibody.Contaminant components may include enzymes, hormones, and otherproteinaceous or nonproteinaceous solutes. In some embodiments, anantibody is purified (1) to greater than 95% by weight of antibody asdetermined by, for example, the Lowry method, and in some embodiments,to greater than 99% by weight: (2) to a degree sufficient to obtain atleast 15 residues of N-terminal or internal amino acid sequence by useof, for example, a spinning cup sequenator, or (3) to homogeneity bySDS-PAGE under reducing or non-reducing conditions using, for example,Coomassie blue or silver stain. An isolated antibody includes theantibody in situ within recombinant cells. Ordinarily, however, anisolated antibody will be prepared by at least one purification step. Apharmaceutical preparation of an isolated antibody typically has lessthan 250 ppm (e.g., less than 200 ppm, 150 ppm. 100 ppm) of host cellproteins (HCP) as determined by an ELISA based HCP assay performed asrecommended by an FDA “Guidance for Industry” document.

As used herein, the term “monoclonal antibody” refers to an antibodyobtained from a population of substantially homogeneous antibodies,i.e., individual antibodies in the population have the same primarysequence except for possible naturally occurring mutations that may bepresent in minor amounts. Monoclonal antibodies are highly specific anddirected against a single antigenic site (i.e., an epitope on humanFcRn). In contrast to polyclonal antibody preparations which typicallyinclude different antibodies directed against different epitopes, eachmonoclonal antibody is directed against a single epitope on the antigen.The modifier “monoclonal” indicates the character of the antibody asbeing obtained from a substantially homogenous population of antibodies,and is not to be construed as requiring production of the antibody byany particular method.

As used herein, the terms “variable region” and “variable domain” referto the portions of the light and heavy chains of an antibody thatinclude amino acid sequences of complementary determining regions (CDRs,e.g., CDR L1, CDR L2. CDR L3, CDR H1, CDR H2, and CDR H3) and frameworkregions (FRs). According to the methods used in this invention, theamino acid positions assigned to CDRs and FRs are defined according toKabat (Sequences of Proteins of Immunological Interest, 5th Ed. PublicHealth Service, National Institutes of Health, Bethesda. Md. (1991)).Using this numbering system, the actual linear amino acid sequence maycontain fewer or additional amino acids corresponding to a shorteningof, or insertion into, a CDR (defined further herein) or FR (definedfurther herein) of the variable region. For example, a heavy chainvariable region may include a single inserted residue (i.e., residue 52aaccording to Kabat) after residue 52 of CDR H2 and inserted residues(i.e., residues 82a, 82b, 82c, etc. according to Kabat) after residue 82of heavy chain FR. The Kabat numbering of residues may be determined fora given antibody by alignment at regions of homology of the sequence ofthe antibody with a “standard” Kabat numbered sequence.

As used herein, the terms “complementary determining regions” and “CDRs”refer to the regions of an antibody variable domain which arehypervariable in sequence and/or form structurally defined loops. A CDRis also known as a hypervariable region. The light chain and heavy chainvariable regions each has three CDRs. The light chain variable regioncontains CDR L1, CDR L2, and CDR L3. The heavy chain variable regioncontains CDR H1, CDR H2, and CDR H3. Each CDR may include amino acidresidues from a complementarity determining region as defined by Kabat(i.e. about residues 24-34 (CDR L1), 50-56 (CDR L2) and 89-97 (CDR L3)in the light chain variable region and about residues 31-35 (CDR H1),50-65 (CDR H2) and 95-102 (CDR H3) in the heavy chain variable region.

As used herein, the term “FcRn” refers a neonatal Fc receptor that bindsto the Fc region of an IgG antibody, e.g., an IgG1 antibody. Anexemplary FcRn is human FcRn having UniProt ID No. P55899. Human FcRn isbelieved to be responsible for maintaining the half-life of IgG bybinding and trafficking constitutively internalized IgG back to the cellsurface for the recycling of IgG.

As used herein, the terms “affinity” and “binding affinity” refer to thestrength of the binding interaction between two molecules. Generally,binding affinity refers to the strength of the sum total of non-covalentinteractions between a single binding site of a molecule and its bindingpartner, such as an isolated antibody and its target (e.g., an isolatedanti-FcRn antibody of the invention and a human FcRn). Unless indicatedotherwise, binding affinity refers to intrinsic binding affinity, whichreflects a 1:1 interaction between members of a binding pair. Thebinding affinity between two molecules is commonly described by thedissociation constant (K_(D)) or the affinity constant (K_(A)). Twomolecules that have low binding affinity for each other generally bindslowly, tend to dissociate easily, and exhibit a large K_(D). Twomolecules that have high affinity for each other generally bind readily,tend to remain bound longer, and exhibit a small K_(D). One method fordetermining the K_(D) of an antibody to human FcRn is described inExample 2 (“the SPR method”). Using this method the K_(D) of N022, N023,N024, N026, and N027 was 31, 31.4, 35.5, 36.5, and 19.3 pM,respectively.

As used herein, the term “inhibit IgG binding to FcRn” refers to theability of an anti-FcRn antibody of the invention to block or inhibitthe binding of IgG (e.g., IgG1) to human FcRn. In some embodiments, ananti-FcRn antibody of the invention binds FcRn, for example, at the siteon human FcRn to which IgG binds. Thus, the anti-FcRn antibody of theinvention is able to inhibit the binding of IgG (e.g., a subject'sautoantibodies) to FcRn. In some embodiments, the molecule (e.g., ananti-FcRn antibody of the invention) substantially or completelyinhibits binding to IgG. In some embodiments, the binding of IgG isreduced by 10%, 20%, 30%, 50%, 70%, 80%, 90%, 95%, or even 100%.

As used herein, the term “hydrophobic amino acid” refers to an aminoacid having relatively low-water solubility. Hydrophobic amino acidsinclude, but are not limited to, leucine, isoleucine, alanine,phenylalanine, valine, and proline. Particularly preferred hydrophobicamino acids in the present invention are alanine, leucine, isoleucine,and valine.

As used herein, the term “polar amino acid” refers to an amino acidhaving a chemical polarity in its side chain induced by atoms withdifferent electronegativity. The polarity of a polar amino acid isdependent on the electronegativity between atoms in the side chain ofthe amino acid and the asymmetry of the structure of the side chain.Polar amino acids include, but are not limited to, serine, threonine,cysteine, methionine, tyrosine, tryptophan, asparagine, and glutamine.Particularly preferred polar amino acids in the present invention areserine, threonine, asparagine, glutamine, cysteine, and tyrosine.

As used herein, the term “acidic amino acid” refers to an amino acidwhose side chain contains a carboxylic acid group having a pKa between3.5 and 4.5. Acidic amino acids include, but are not limited to,aspartic acid and glutamic acid.

As used herein, the term “basic amino acid” refers to an amino acidwhose side chain contains an amino group having a pKa between 9.5 and13. Basic amino acids include, but are not limited to, histidine,lysine, and arginine.

As used herein, the term “percent (%) identity” refers to the percentageof amino acid (or nucleic acid) residues of a candidate sequence, e.g.,an anti-FcRn antibody of the invention, that are identical to the aminoacid (or nucleic acid) residues of a reference sequence, e.g., awild-type anti-FcRn antibody, after aligning the sequences andintroducing gaps, if necessary, to achieve the maximum percent identity(i.e., gaps can be introduced in one or both of the candidate andreference sequences for optimal alignment and non-homologous sequencescan be disregarded for comparison purposes). Alignment for purposes ofdetermining percent identity can be achieved in various ways that arewithin the skill in the art, for instance, using publicly availablecomputer software such as BLAST, ALIGN, or Megalign (DNASTAR) software.Those skilled in the art can determine appropriate parameters formeasuring alignment, including any algorithms needed to achieve maximalalignment over the full length of the sequences being compared. In someembodiments, the percent amino acid (or nucleic acid) sequence identityof a given candidate sequence to, with, or against a given referencesequence (which can alternatively be phrased as a given candidatesequence that has or includes a certain percent amino acid (or nucleicacid) sequence identity to, with, or against a given reference sequence)is calculated as follows:

100×(fraction of A/B)

where A is the number of amino acid (or nucleic acid) residues scored asidentical in the alignment of the candidate sequence and the referencesequence, and where B is the total number of amino acid (or nucleicacid) residues in the reference sequence. In some embodiments where thelength of the candidate sequence does not equal to the length of thereference sequence, the percent amino acid (or nucleic acid) sequenceidentity of the candidate sequence to the reference sequence would notequal to the percent amino acid (or nucleic acid) sequence identity ofthe reference sequence to the candidate sequence.

In particular embodiments, a reference sequence aligned for comparisonwith a candidate sequence may show that the candidate sequence exhibitsfrom 50% to 100% identity across the full length of the candidatesequence or a selected portion of contiguous amino acid (or nucleicacid) residues of the candidate sequence. The length of the candidatesequence aligned for comparison purpose is at least 30%, e.g., at least40%, e.g., at least 50%, 60%, 70%, 80%, 90%, or 100% of the length ofthe reference sequence. When a position in the candidate sequence isoccupied by the same amino acid (or nucleic acid) residue as thecorresponding position in the reference sequence, then the molecules areidentical at that position.

As used herein, the term “host cell” refers to a vehicle that includesthe necessary cellular components, e.g., organelles, needed to expressproteins from their corresponding nucleic acids. The nucleic acids aretypically included in nucleic acid vectors that can be introduced intothe host cell by conventional techniques known in the art (e.g.,transformation, transfection, electroporation, calcium phosphateprecipitation, direct microinjection, etc.). A host cell may be aprokaryotic cell, e.g., a bacterial cell, or a eukaryotic cell, e.g., amammalian cell (e.g., a CHO cell). As described herein, a host cell isused to express one or more polypeptides encoding anti-FcRn antibodiesof the invention.

As used herein, the term “vector” refers to a nucleic acid moleculecapable of transporting another nucleic acid molecule to which it hasbeen linked. One type of vector is a “plasmid,” which refers to acircular double stranded DNA loop into which additional DNA segments maybe ligated. Another type of vector is a phage vector. Another type ofvector is a viral vector, wherein additional DNA segments may be ligatedinto the viral genome. Certain vectors are capable of autonomousreplication in a host cell into which they are introduced (e.g.,bacterial vectors having a bacterial origin of replication and episomalmammalian vectors). Other vectors (e.g., non-episomal mammalian vectors)can be integrated into the genome of a host cell upon introduction intothe host cell, and thereby are replicated along with the host genome.Moreover, certain vectors are capable of directing the expression ofgenes to which they are operatively linked. Such vectors are referred toherein as “recombinant expression vectors” (or simply, “recombinantvectors”). In general, expression vectors of utility in recombinant DNAtechniques are often in the form of plasmids.

As used herein, the term “subject” refers to a mammal, e.g., preferablya human. Mammals include, but are not limited to, humans and domesticand farm animals, such as monkeys (e.g., a cynomolgus monkey), mice,dogs, cats, horses, and cows, etc.

As used herein, the term “pharmaceutical composition” refers to amedicinal or pharmaceutical formulation that contains an activeingredient as well as one or more excipients and diluents to enable theactive ingredient suitable for the method of administration. Thepharmaceutical composition of the present invention includespharmaceutically acceptable components that are compatible with theanti-FcRn antibody. The pharmaceutical composition may be in aqueousform for intravenous or subcutaneous administration or in tablet orcapsule form for oral administration.

As used herein, the term “pharmaceutically acceptable carrier” refers toan excipient or diluent in a pharmaceutical composition. Thepharmaceutically acceptable carrier must be compatible with the otheringredients of the formulation and not deleterious to the recipient. Inthe present invention, the pharmaceutically acceptable carrier mustprovide adequate pharmaceutical stability to the Fc construct. Thenature of the carrier differs with the mode of administration. Forexample, for intravenous administration, an aqueous solution carrier isgenerally used; for oral administration, a solid carrier is preferred.

As used herein, the term “therapeutically effective amount” refers to anamount, e.g., pharmaceutical dose, effective in inducing a desiredbiological effect in a subject or patient or in treating a patienthaving a condition or disorder described herein. It is also to beunderstood herein that a “therapeutically effective amount” may beinterpreted as an amount giving a desired therapeutic effect, eithertaken in one dose or in any dosage or route, taken alone or incombination with other therapeutic agents.

DESCRIPTION OF THE DRAWINGS

FIG. 1 includes two graphs and a table that show IgG competitive bindingof antibodies N022-N024, N026, and N027 to human or cynomolgus monkeyFcRn at pH 6.0.

FIG. 2 includes graphs that show the effects of antibodies N023, N024,N026, and N027 on IgG catabolism in mice.

FIG. 3 includes graphs that show the dose-dependent effects of antibodyN027 on IgG levels and target occupancy in mice.

FIG. 4 includes graphs that show the selective induction of IgGcatabolism and target occupancy in cynomolgus monkeys followingadministration of different doses of antibody N027.

FIG. 5 includes a graph that shows the biodistribution of N027 in mice.

FIG. 6 includes an experimental timeline and a graph that shows theefficacy of N027 in a mouse collagen antibody-induced arthritis model.

FIG. 7 includes an experimental timeline and two graphs that show theefficacy of N027 in a mouse chronic idiopathic thrombocytopenia purpura(ITP) model.

DETAILED DESCRIPTION OF THE INVENTION

The present invention features isolated antibodies that bind to humanneonatal Fc receptor (FcRn) with high affinity. The present inventionfeatures anti-FcRn antibodies, methods and compositions for preparinganti-FcRn antibodies, and methods for blocking FcRn activity, reducingimmune complex-based activation of an immune response, and treatingimmunological diseases.

I. Anti-FcRn Antibodies

In general, the invention features isolated antibodies that bind to thehuman FcRn with high affinity. An anti-FcRn antibody of the inventionrefers to an antibody that can bind to human FcRn and inhibit IgG (e.g.,IgG autoantibodies) binding to FcRn. In some embodiments, the antibodyis a monoclonal antibody. In other embodiments, the antibody is apolyclonal antibody. In some embodiments, the antibody is selected fromthe group consisting of a chimeric antibody, an affinity maturedantibody, a humanized antibody, and a human antibody. In certainembodiments, the antibody is an antibody fragment, e.g., a Fab, Fab′,Fab′-SH, F(ab′)₂, or scFv.

In some embodiments, the antibody is a chimeric antibody. For example,an antibody contains antigen binding sequences from a non-human donorgrafted to a heterologous non-human, human, or humanized sequence (e.g.,framework and/or constant domain sequences). In one embodiment, thenon-human donor is a mouse. In another embodiment, an antigen bindingsequence is synthetic, e.g., obtained by mutagenesis (e.g., phagedisplay screening, etc.). In a further embodiment, a chimeric antibodyhas non-human (e.g., mouse) variable regions and human constant regions.In one example, a mouse light chain variable region is fused to a humanK light chain. In another example, a mouse heavy chain variable regionis fused to a human IgG1 constant region.

In one aspect, the invention features an isolated antibody capable ofbinding to human FcRn. The isolated antibody contains: (1) a light chainvariable region that includes a CDR L1, a CDR L2, and a CDR L3 and (2) aheavy chain variable region that includes a CDR H1, a CDR H2, and a CDRH3, wherein the CDR L1 has a sequence having at least 92% identity tothe sequence of TGTGSDVGSYNLVS (SEQ ID NO: 1), the CDR L2 has a sequencehaving at least 85% identity to the sequence of GDSERPS (SEQ ID NO: 2),the CDR L3 has a sequence having at least 90% identity to the sequenceof SSYAGSGIYV (SEQ ID NO: 3), the CDR H1 has a sequence having at least80% identity to the sequence of TYAMG (SEQ ID NO: 4), DYAMG (SEQ ID NO:5), or NYAMG (SEQ ID NO: 6), the CDR H2 has a sequence having at least92% identity to the sequence of SIGSSGAQTRYADS (SEQ ID NO: 7),SIGASGSQTRYADS (SEQ ID NO: 8), SIGASGAQTRYADS (SEQ ID NO: 9), orSIGASGGQTRYADS (SEQ ID NO: 10), and the CDR H3 has a sequence having atleast 85% identity to the sequence of LAIGDSY (SEQ ID NO: 11). In someembodiments, the antibody binds human FcRn with a K_(D) of less than200, 150, 100, 50, or 40 pM. In some embodiments, the antibody bindshuman FcRn with a K_(D) that is less than or equal to that of anantibody having the light chain variable region and heavy chain variableregion of N022, N023, N024, N026, or N027, and further having the sameFc region as the antibody being compared.

In some embodiments, an isolated antibody of the invention has a CDR L1that has the sequence of X₁GTGSDVGSYNX₂VS (SEQ ID NO: 12), a CDR L2 thathas the sequence of GDX₃X₄RPS (SEQ ID NO: 13), a CDR L3 that has thesequence of X₅SYX₆GSGIYV (SEQ ID NO: 14), a CDR H1 that has the sequenceof Z₁YAMG (SEQ ID NO: 15), a CDR H2 that has the sequence ofSIGZ₂SGZ₃QTZ₄YADS (SEQ ID NO: 16), and a CDR H3 that has the sequence ofLAZ₅Z₆DSY (SEQ ID NO: 17), where X₁ is a polar or hydrophobic amino acid(e.g., preferably T, A, S, or I), X₂ is a hydrophobic amino acid (e.g.,preferably L or I), X₃ is a polar amino acid (e.g., preferably S, N, orT). X₄ is a polar or acidic amino acid (e.g., preferably Q, E, or N), X₅is a polar or hydrophobic amino acid (e.g., preferably C, S, I, or Y),X₆ is a hydrophobic amino acid (e.g., preferably A or V), Z₁ is a polaror acidic amino acid (e.g., preferably E, T, D, or N), Z₂ is a polar orhydrophobic amino acid (e.g., preferably S or A), Z₃ is G, S, or A, Z₄is a basic amino acid (e.g., preferably K or R), Z₅ is a hydrophobic orbasic amino acid (e.g., preferably I, L, or H), and Z₆ is G, S, D, Q, orH, and where the antibody binds human FcRn with a K_(D) of less than200, 150, 100, 50, or 40 pM.

In other embodiments, an isolated antibody of the invention has a CDR L1that has the sequence of TGTGSDVGSYNLVS (SEQ ID NO: 1), a CDR L2 thathas the sequence of GDSERPS (SEQ ID NO: 2), a CDR L3 that has thesequence of SSYAGSGIYV (SEQ ID NO: 3), a CDR H1 that has the sequence ofZ₁YAMG (SEQ ID NO: 15), a CDR H2 that has the sequence ofSIGZ₂SGZ₃QTRYADS (SEQ ID NO: 18), and a CDR H3 that has the sequence ofLAIGDSY (SEQ ID NO: 11), where Z₁ is T, D, or N, Z₂ is S or A, and Z₃ isG, S or A.

Table 1 shows the amino acid sequences of the light and heavy chaincomplementary determining regions (CDRs) of some exemplary anti-FcRnantibodies of the invention.

TABLE 1 Anti- FcRn antibody CDR L1 CDR L2 CDR L3 CDR H1 CDR H2 CDR H3N022 TGTGSDVGSYNLVS GDSERPS SSYAGSGIYV TYAMG SIGSSGAQTRYADS LAIGDSY(SEQ ID NO: 1) (SEQ ID NO: 2) (SEQ ID NO: 3) (SEQ ID NO: 4)(SEQ ID NO: 7) (SEQ ID NO: 11) N023 TGTGSDVGSYNLVS GDSERPS SSYAGSGIYVDYAMG SIGASGSQTRYADS LAIGDSY (SEQ ID NO: 1) (SEQ ID NO: 2)(SEQ ID NO: 3) (SEQ ID NO: 5) (SEQ ID NO: 8) (SEQ ID NO: 11) N024TGTGSDVGSYNLVS GDSERPS SSYAGSGIYV NYAMG SIGASGAQTRYADS LAIGDSY(SEQ ID NO: 1) (SEQ ID NO: 2) (SEQ ID NO: 3) (SEQ ID NO: 6)(SEQ ID NO: 9) (SEQ ID NO: 11) N026 TGTGSDVGSYNLVS GDSERPS SSYAGSGIYVTYAMG SIGASGGQTRYADS LAIGDSY (SEQ ID NO: 1) (SEQ ID NO: 2)(SEQ ID NO: 3) (SEQ ID NO: 4) (SEQ ID NO: 10) (SEQ ID NO: 11) N027TGTGSDVGSYNLVS GDSERPS SSYAGSGIYV TYAMG SIGASGSQTRYADS LAIGDSY(SEQ ID NO: 1) (SEQ ID NO: 2) (SEQ ID NO: 3) (SEQ ID NO: 4)(SEQ ID NO: 8) (SEQ ID NO: 11)

Table 2 shows the SEQ ID NOs of the light and heavy chain variableregions of these exemplary anti-FcRn antibodies of the invention.

TABLE 2 Anti-FcRn Light Chain Heavy Chain antibody Variable RegionVariable Region N022 SEQ ID NO: 19 SEQ ID NO: 20 N023 SEQ ID NO: 21 N024SEQ ID NO: 22 N026 SEQ ID NO: 23 N027 SEQ ID NO: 24

In some embodiments, the light chain variable region of an isolatedantibody of the invention has a sequence having at least 90% identity tothe sequence of

(SEQ ID NO: 19) QSALTQPASVSGSPGQSITISCTGTGSDVGSYNLVSWYQQHPGKAPKLMIYGDSERPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYAGSGIYVFGTGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHKSYSCQVT HEGSTVEKTVAPTECS.

In some embodiments, the heavy chain variable region of an isolatedantibody of the invention has a sequence having at least 90% identity tothe sequence of

(SEQ ID NO: 20) EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMGWVRQAPGKGLEWVSSIGSSGAQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG.

In some embodiments, the heavy chain variable region of an isolatedantibody of the invention has a sequence having at least 90% identity tothe sequence of

(SEQ ID NO: 21) EVQLLESGGGLVQPGGSLRLSCAASGFTFSDYAMGWVRQAPGKGLEWVSSIGASGSQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYGARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG.

In some embodiments, the heavy chain variable region of an isolatedantibody of the invention has a sequence having at least 90% identity tothe sequence of

(SEQ ID NO: 22) EVQLLESGGGLVQPGGSLRLSCAASGFTFSNYAMGWVRQAPGKGLEWVSSIGASGAQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG.

In other embodiments, the heavy chain variable region of an isolatedantibody of the invention has a sequence having at least 90% identity tothe sequence of

(SEQ ID NO: 23) EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMGWVRQAPGKGLEWVSSIGASGGQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG.

In yet other embodiments, the heavy chain variable region of an isolatedantibody of the invention has a sequence having at least 90% identity tothe sequence of

(SEQ ID NO: 24) EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMGWVRQAPGKGLEWVSSIGASGSQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG.

The invention features an isolated antibody including a light chainvariable region and a heavy chain variable region, where the light chainvariable region has a sequence having at least 90% identity to thesequence of

(SEQ ID NO: 19) QSALTQPASVSGSPGQSITISCTGTGSDVGSYNLVSWYQQHPGKAPKLMIYGDSERPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYAGSGIYVFGTGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHKSYS CQVTHEGSTVEKTVAPTECS;and the heavy chain variable region has a sequence having at least 90%identity to the sequence of

(SEQ ID NO: 20) EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMGWVRQAPGKGLEWVSSIGSSGAQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG.

The invention features an isolated antibody including a light chainvariable region and a heavy chain variable region, where the light chainvariable region has a sequence having at least 90% identity to thesequence of

(SEQ ID NO: 19) QSALTQPASVSGSPGQSITISCTGTGSDVGSYNLVSWYQQHPGKAPKLMIYGDSERPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYAGSGIYVFGTGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHKSYS CQVTHEGSTVEKTVAPTECS;and the heavy chain variable region has a sequence having at least 90%identity to the sequence of

(SEQ ID NO: 21) EVQLLESGGGLVQPGGSLRLSCAASGFTFSDYAMGWVRQAPGKGLEWVSSIGASGSQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYGARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG.

The invention features an isolated antibody including a light chainvariable region and a heavy chain variable region, where the light chainvariable region has a sequence having at least 90% identity to thesequence of

(SEQ ID NO: 19) QSALTQPASVSGSPGQSITISCTGTGSDVGSYNLVSWYQQHPGKAPKLMIYGDSERPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYAGSGIYVFGTGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHKSYS CQVTHEGSTVEKTVAPTECS;and the heavy chain variable region has a sequence having at least 90%identity to the sequence of

(SEQ ID NO: 22) EVQLLESGGGLVQPGGSLRLSCAASGFTFSNYAMGWVRQAPGKGLEWVSSIGASGAQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG.

The invention features an isolated antibody including a light chainvariable region and a heavy chain variable region, where the light chainvariable region has a sequence having at least 90% identity to thesequence of

(SEQ ID NO: 19) QSALTQPASVSGSPGQSITISCTGTGSDVGSYNLVSWYQQHPGKAPKLMIYGDSERPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYAGSGIYVFGTGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHKSYS CQVTHEGSTVEKTVAPTECS;and the heavy chain variable region has a sequence having at least 90%identity to the sequence of

(SEQ ID NO: 23) EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMGWVRQAPGKGLEWVSSIGASGGQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG.

The invention features an isolated antibody including a light chainvariable region and a heavy chain variable region, where the light chainvariable region has a sequence having at least 90% identity to thesequence of

(SEQ ID NO: 19) QSALTQPASVSGSPGQSITISCTGTGSDVGSYNLVSWYQQHPGKAPKLMIYGDSERPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYAGSGIYVFGTGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHKSYS CQVTHEGSTVEKTVAPTECS;and the heavy chain variable region has a sequence having at least 90%identity to the sequence of

(SEQ ID NO: 24) EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMGWVRQAPGKGLEWVSSIGASGSQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG.

Furthermore, in any of the anti-FcRn antibodies described herein, theheavy chain variable region of the antibody has a sequence having atleast 95%, 97%, 99%, or 100% identity to the sequence of any one of SEQID NOs: 20-24. In any of the anti-FcRn antibodies described herein, thelight chain variable region has a sequence having at least 95%, 97%,99%, or 100% identity to the sequence of SEQ ID NO: 19.

The antibodies of the invention may further contain amino acidsubstitutions, additions, and/or deletions outside of the CDRs (i.e., inframework regions (FRs)). In some embodiments, the antibodies of theinvention may further include any one or more of the following aminoacid substitutions: A23V, S30R, L80V, A84T, E85D, A93V, relative to thesequence of any one of SEQ ID NOs: 20-24, and Q38H, V58I, and G99D,relative to the sequence of SEQ ID NO: 19.

In some embodiments, the antibodies of the invention may include aminoacid substitutions, additions, and/or deletions in the constant regions(e.g., Fc region) of the antibody that, e.g., lead to decreased effectorfunction, e.g., decreased complement-dependent cytolysis (CDC),antibody-dependent cell-mediated cytolysis (ADCC), and/orantibody-dependent cell-mediated phagocytosis (ADCP), and/or decreasedB-cell killing. The constant regions are not involved directly inbinding an antibody to its target, but exhibit various effectorfunctions, such as participation of the antibody in antibody-dependentcellular toxicity. In some embodiments, the antibodies of the inventionare characterized by decreased binding (i.e., absence of binding) tohuman complement factor C1q and/or human Fc receptor on natural killer(NK) cells. In other embodiments, the antibodies of the invention arecharacterized by decreased binding (i.e., absence of binding) to humanFcγRI, FcγRIIA, and/or FcγRIIIA. To alter or reduce anantibody-dependent effector function, such as CDC, ADCC, ADCP, and/orB-cell killing, antibodies of the invention may be of the IgG class andcontain one or more amino acid substitutions E233, L234, G236, D265,D270, N297, E318, K320, K322, A327, A330, P331, and/or P329 (numberingaccording to the EU index of Kabat (Sequences of Proteins ofImmunological Interest, 5th Ed. Public Health Service, NationalInstitutes of Health, Bethesda, Md. (1991))). In some embodiments, theantibodies contain the mutations L234AA/235A or D265A/N297A. Preferably,an anti-FcRn antibody of the invention contains amino acid substitutionN297A, relative to the sequence of any one of SEQ ID NOs: 20-24, suchthat the antibody of the invention is changed to an aglycosylated form.The resulting effectorless antibody shows very little binding tocomplement or Fc receptors (i.e., complement C1q binding), indicatinglow CDC potential.

In other embodiments, the antibodies of the invention may include thosehaving specific amino acid changes that improve stability of theantibody.

Moreover, in other embodiments, to minimize potential immunogenicity,some antibodies of the invention, e.g., N024, N026, and N027, mayundergo an allotype change from G1m17.1 to G1m17 by substituting aminoacids D355 and L357 (relative to the sequence of any one of SEQ ID NOs:20-24) to glutamic acid and methionine, respectively.

In other embodiments, the antibodies of the invention, e.g., N022-N024,N026, and N027, do not contain a C-terminal lysine at residue 446,relative to the sequence of any one of SEQ ID NOs: 20-24.

The invention features an isolated antibody containing a light chainvariable region and a heavy chain variable region, wherein the lightchain variable region has the sequence of

(SEQ ID NO: 19) QSALTQPASVSGSPGQSITISCTGTGSDVGSYNLVSWYQQHPGKAPKLMIYGDSERPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYAGSGIYVFGTGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHKSYS CQVTHEGSTVEKTVAPTECS;and the heavy chain variable region has the sequence of

(SEQ ID NO: 20) EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMGWVRQAPGKGLEWVSSIGSSGAQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG.

The invention features an isolated antibody containing a light chainvariable region and a heavy chain variable region, wherein the lightchain variable region has the sequence of

(SEQ ID NO: 19) QSALTQPASVSGSPGQSITISCTGTGSDVGSYNLVSWYQQHPGKAPKLMIYGDSERPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYAGSGIYVFGTGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHKSYS CQVTHEGSTVEKTVAPTECS;and the heavy chain variable region has the sequence of

(SEQ ID NO: 21) EVQLLESGGGLVQPGGSLRLSCAASGFTFSDYAMGWVRQAPGKGLEWVSSIGASGSQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS LSPG. 

The invention features an isolated antibody containing a light chainvariable region and a heavy chain variable region, wherein the lightchain variable region has the sequence of

(SEQ ID NO: 19) QSALTQPASVSGSPGQSITISCTGTGSDVGSYNLVSWYQQHPGKAPKLMIYGDSERPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYAGSGIYVFGTGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHKSYS CQVTHEGSTVEKTVAPTECS;and the heavy chain variable region has the sequence of

(SEQ ID NO: 22) EVQLLESGGGLVQPGGSLRLSCAASGFTFSNYAMGWVRQAPGKGLEWVSSIGASGAQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS LSPG.

The invention features an isolated antibody containing a light chainvariable region and a heavy chain variable region, wherein the lightchain variable region has the sequence of

(SEQ ID NO: 19) QSALTQPASVSGSPGQSITISCTGTGSDVGSYNLVSWYQQHPGKAPKLMIYGDSERPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYAGSGIYVFGTGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHKSYS CQVTHEGSTVEKTVAPTECS;and the heavy chain variable region has the sequence of

(SEQ ID NO: 23) EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMGWVRQAPGKGLEWVSSIGASGGQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS LSPG.

The invention features an isolated antibody containing a light chainvariable region and a heavy chain variable region, wherein the lightchain variable region has the sequence of

(SEQ ID NO: 19) QSALTQPASVSGSPGQSITISCTGTGSDVGSYNLVSWYQQHPGKAPKLMIYGDSERPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYAGSGIYVFGTGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHKSYS CQVTHEGSTVEKTVAPTECS;and the heavy chain variable region has the sequence of

(SEQ ID NO: 24) EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMGWVRQAPGKGLEWVSSIGASGSQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS LSPG.

In yet other embodiments, the antibodies of the invention are sialylatedantibodies.

In any of the anti-FcRn antibodies described herein, in someembodiments, the antibody binds mouse or rat FcRn with a K_(D) of lessthan 200, 150, 100, 50, or 40 pM.

In any of the anti-FcRn antibodies described herein, in someembodiments, the antibody binds to human FcRn with an affinity ofbetween 1-100, 5-150, 5-100, 5-75, 5-50, 10-50, or 10-40 pM.

The anti-FcRn antibodies of the invention may be of immunoglobulinantibody isotype IgG, IgE, IgM, IgA, or IgD. Preferably, the anti-FcRnantibodies are of immunoglobulin antibody isotype IgG. The anti-FcRnantibodies may also be of any immunoglobulin antibody isotypesubclasses. For example, the anti-FcRn antibodies may be of IgG subclassIgG1. IgG2, IgG3, or IgG4. Preferably, the anti-FcRn antibodies are ofsubclass IgG1. In particular, the anti-FcRn antibodies of the inventioncontain an IgG G1m17 or G1m17.1 allotype heavy chain. In someembodiments, the light chain of the anti-FcRn antibodies may be a κlight chain, a λ light chain, or a κ-λ chimeric light chain. Inpreferred embodiments, the anti-FcRn antibodies of the invention containa full-length λ light chain.

In some embodiments, the antibodies of the invention are monoclonal. Theantibodies of the invention may also be polyclonal, chimeric, humanizedor fully human. In some embodiments, the antibody of the invention maybe affinity matured. In other embodiments, the antibody of the inventionmay be an antibody fragment.

Without being bound by theory, it is believed that the anti-FcRnantibodies of the invention compete with and inhibit the binding of IgGto human FcRn. Epitope mapping by hydrogen-deuterium exchange of theantibodies of the invention indicates that the antibodies bind to anepitope on FcRn located in and/or adjacent to the Fc-FcRn interactioninterface, which suggests that the antibodies of the invention block IgGbinding to FcRn by direction inhibition. Furthermore, the epitope-mappedbinding site is distant from the albumin-binding site of FcRn.Accordingly, serum albumin-binding should not be inhibited and serumalbumin levels should not be decreased. Indeed, experimental evidenceshows mouse albumin levels remained constant after anti-FcRn antibodyadministration, indicating that albumin recycling is not disturbed byantibody binding to FcRn.

II. Sialylated Anti-FcRn Antibodies

In some embodiments, the glycosylation site of the Fc region ofanti-FcRn antibodies of the invention is at least 25%, 50%, 75% or moresialylated, on a mole basis. The antibodies of the invention may besialylated with a sialyltransferase (ST6 Gal-I), which sialylates asubstrate in an ordered fashion. Specifically, under certain conditions,ST6 sialyltransferase catalyzes addition of a sialic acid on the α1,3arm of glycans on the Fc region of anti-FcRn antibodies, followed byaddition of a second sialic acid on the α1,6 arm, followed by removal ofsialic acid from the α1,3 arm.

Isolated anti-FcRn antibodies of the invention may be sialylated duringproduction in the manufacturing host cells (e.g., mammalian cells, e.g.,mammalian cells co-transfected with—or overexpressing—an ST6sialyltransferase). In other embodiments, isolated anti-FcRn antibodiesof the invention may be sialylated in vitro, post purification from themanufacturing host cell, e.g., enzymatically or through chemicalconjugation. Methods of producing sialylated anti-FcRn antibodies aredescribed in PCT Publication WO2014/179601.

III. FcRn Inhibition

FcRn is a type I transmembrane protein that functions as an IgG- andserum albumin-binding, intracellular vesicular trafficking protein. FcRnis expressed in endothelial cells, luminal epithelial cells,hepatocytes, podocytes, granulocytes, monocytes, macrophages, dendriticcells, and NK cells, but not on B or T cells. FcRn maintains thehalf-life of IgG by binding and trafficking constitutively internalizedIgG back to the cell surface. Binding of both Fc and serum albumin byFcRn occurs in the early endosome at pH 6.0, followed by sorting of theFcRn into vesicles, which traffic the FcRn-bound IgG or albumin back tothe cell surface where FcRn rapidly releases the IgG or albumin at pH7.4. This trafficking cycle maintains the half-life of IgG and albuminby recycling both into the circulation and preventing trafficking to thelysosomes for degradation. FcRn also captures internalized IgG Fc inepithelial cells and transports them bidirectionally to the opposingapical or basolateral membranes. This function allows IgG to traffic tothe lumen of organs such as the gastrointestinal tract or the transportof IgG or IgG-antigen complexes from the lumen to the vasculature orlymphoid tissues in the stromal layers.

In order to study the contribution of FcRn to IgG homeostasis, mice havebeen engineered so that parts of the light and heavy chains of FcRn havebeen “knocked out” so that these proteins are not expressed (Junghans etal., Proc Natl Acad Sci USA 93:5512, 1996). In these mice, the serumhalf-life and concentrations of IgG were dramatically reduced,suggesting an FcRn-dependent mechanism of IgG homeostasis. Studies inrodent models, such as the one discussed above, suggest that blockage ofFcRn can increase IgG catabolism, including that of pathogenicautoantibodies, thereby inhibiting disease (e.g., an autoimmune disease)development. FcRn may also contribute to antigen presentation throughtrafficking of immune complexes to antigen degradation and MHC loadingcompartments.

The present invention provides isolated anti-FcRn antibodies that bindto human FcRn with high affinity. The anti-FcRn antibodies of theinvention compete with and effectively inhibit the binding of otheranti-FcRn antibodies (e.g., IgG, IgG autoantibodies) to FcRn, therebyincreasing the catabolism and decreasing the half-life of otheranti-FcRn antibodies (e.g., IgG, IgG autoantibodies). The anti-FcRnantibodies of the invention may be used in a method of treating orreducing immune complex-based activation of an immune response in asubject, such as an immune response caused by autoantibodies in anautoimmune disease.

IV. Vectors, Host Cells, and Antibody Production

The anti-FcRn antibodies of the invention can be produced from a hostcell. A host cell refers to a vehicle that includes the necessarycellular components, e.g., organelles, needed to express thepolypeptides and constructs described herein from their correspondingnucleic acids. The nucleic acids may be included in nucleic acid vectorsthat can be introduced into the host cell by conventional techniquesknown in the art (e.g., transformation, transfection, electroporation,calcium phosphate precipitation, direct microinjection, infection, etc).The choice of nucleic acid vectors depends in part on the host cells tobe used. Generally, preferred hostcells are of either prokaryotic (e.g.,bacterial) or eukaryotic (e.g., mammalian) origin.

Nucleic Acid Vector Construction and Host Cells

A nucleic acid sequence encoding the amino acid sequence of an anti-FcRnantibody of the invention may be prepared by a variety of methods knownin the art. These methods include, but are not limited to,oligonucleotide-mediated (or site-directed) mutagenesis and PCRmutagenesis. A nucleic acid molecule encoding an anti-FcRn antibody ofthe invention may be obtained using standard techniques, e.g., genesynthesis. Alternatively, a nucleic acid molecule encoding a wild-typeanti-FcRn antibody may be mutated to contain specific amino acidsubstitutions using standard techniques in the art, e.g., QuikChange™mutagenesis. Nucleic acid molecules can be synthesized using anucleotide synthesizer or PCR techniques.

Nucleic acid sequences encoding anti-FcRn antibodies of the inventionmay be inserted into a vector capable of replicating and expressing thenucleic acid molecules in prokaryotic or eukaryotic host cells. Manyvectors are available in the art and can be used for the purpose of theinvention. Each vector may contain various components that may beadjusted and optimized for compatibility with the particular host cell.For example, the vector components may include, but are not limited to,an origin of replication, a selection marker gene, a promoter, aribosome binding site, a signal sequence, the nucleic acid sequenceencoding protein of interest, and a transcription termination sequence.

In some embodiments, mammalian cells are used as host cells for theinvention. Examples of mammalian cell types include, but are not limitedto, human embryonic kidney (HEK) (e.g., HEK293, HEK 293F), Chinesehamster ovary (CHO), HeLa, COS, PC3, Vero, MC3T3, NS0, Sp2/0, VERY, BHK,MDCK, W138, BT483, Hs578T, HTB2, BT20, T47D, NS0 (a murine myeloma cellline that does not endogenously produce any immunoglobulin chains),CRL7O3O, and HsS78Bst cells. In other embodiments, E. coli cells areused as host cells for the invention. Examples of E. coli strainsinclude, but are not limited to, E. coli 294 (ATCC®31,446), E. coli λ1776 (ATCC® 31,537, E. coli BL21 (DE3) (ATCC®BAA-1025), and E. coliRV308 (ATCC®31,608). Different host cells have characteristic andspecific mechanisms for the posttranslational processing andmodification of protein products. Appropriate cell lines or host systemsmay be chosen to ensure the correct modification and processing of theanti-FcRn antibody expressed. The above-described expression vectors maybe introduced into appropriate host cells using conventional techniquesin the art, e.g., transformation, transfection, electroporation, calciumphosphate precipitation, and direct microinjection. Once the vectors areintroduced into host cells for protein production, host cells arecultured in conventional nutrient media modified as appropriate forinducing promoters, selecting transformants, or amplifying the genesencoding the desired sequences. Methods for expression of therapeuticproteins are known in the art, see, for example, Paulina Balbas, ArgeliaLorence (eds.) Recombinant Gene Expression: Reviews and Protocols(Methods in Molecular Biology), Humana Press: 2nd ed. 2004 (Jul. 20,2004) and Vladimir Voynov and Justin A. Caravella (eds.) TherapeuticProteins: Methods and Protocols (Methods in Molecular Biology) HumanaPress; 2nd ed. 2012 (Jun. 28, 2012).

Protein Production, Recovery, and Purification

Host cells used to produce the anti-FcRn antibodies of the invention maybe grown in media known in the art and suitable for culturing of theselected host cells. Examples of suitable media for mammalian host cellsinclude Minimal Essential Medium (MEM), Dulbecco's Modified Eagle'sMedium (DMEM), Expi293™ Expression Medium, DMEM with supplemented fetalbovine serum (FBS), and RPMI-1640. Examples of suitable media forbacterial host cells include Luria broth (LB) plus necessarysupplements, such as a selection agent, e.g., ampicillin. Host cells arecultured at suitable temperatures, such as from about 20° C. to about39° C., e.g., from 25° C. to about 37° C., preferably 37° C., and CO₂levels, such as 5 to 10% (preferably 8%). The pH of the medium isgenerally from about 6.8 to 7.4, e.g., 7.0, depending mainly on the hostorganism. If an inducible promoter is used in the expression vector ofthe invention, protein expression is induced under conditions suitablefor the activation of the promoter.

Protein recovery typically involves disrupting the host cell, generallyby such means as osmotic shock, sonication, or lysis. Once the cells aredisrupted, cell debris may be removed by centrifugation or filtration.The proteins may be further purified. An anti-FcRn antibody of theinvention may be purified by any method known in the art of proteinpurification, for example, by protein A affinity, other chromatography(e.g., ion exchange, affinity, and size-exclusion columnchromatography), centrifugation, differential solubility, or by anyother standard technique for the purification of proteins. (see ProcessScale Purification of Antibodies, Uwe Gottschalk (ed.) John Wiley &Sons, Inc., 2009). In some instances, an anti-FcRn antibody can beconjugated to marker sequences, such as a peptide to facilitatepurification. An example of a marker amino acid sequence is ahexa-histidine peptide (His-tag), which binds to nickel-functionalizedagarose affinity column with micromolar affinity. Other peptide tagsuseful for purification include, but are not limited to, thehemagglutinin “HA” tag, which corresponds to an epitope derived from theinfluenza hemagglutinin protein.

Alternatively, anti-FcRn antibodies of the invention can be produced bythe cells of a subject (e.g., a human), e.g., in the context of therapy,by administrating a vector (e.g., a retroviral vector, adenoviralvector, poxviral vector (e.g., vaccinia viral vector, such as ModifiedVaccinia Ankara (MVA)), adeno-associated viral vector, and alphaviralvector) containing a nucleic acid molecule encoding the anti-FcRnantibody of the invention. The vector, once inside a cell of the subject(e.g., by transformation, transfection, electroporation, calciumphosphate precipitation, direct microinjection, infection, etc) willpromote expression of the anti-FcRn antibody, which is then secretedfrom the cell. If treatment of a disease or disorder is the desiredoutcome, no further action may be required. If collection of the proteinis desired, blood may be collected from the subject and the proteinpurified from the blood by methods known in the art.

V. Pharmaceutical Compositions and Preparations

The invention features pharmaceutical compositions that include one ormore anti-FcRn antibodies described herein. In some embodiments,pharmaceutical compositions of the invention contain one or moreantibodies of the invention, e.g., N022-N024, N026, and N027, as thetherapeutic proteins. In other embodiments, pharmaceutical compositionsof the invention containing one or more antibodies of the invention,e.g., N022-N024, N026, and N027, may be used in combination with otheragents (e.g., therapeutic biologics and/or small molecules) orcompositions in a therapy. In addition to a therapeutically effectiveamount of the antibody, the pharmaceutical compositions may contain oneor more pharmaceutically acceptable carriers or excipients, which can beformulated by methods known to those skilled in the art.

Acceptable carriers and excipients in the pharmaceutical compositionsare nontoxic to recipients at the dosages and concentrations employed.Acceptable carriers and excipients may include buffers, antioxidants,preservatives, polymers, amino acids, and carbohydrates. Pharmaceuticalcompositions of the invention can be administered parenterally in theform of an injectable formulation. Pharmaceutical compositions forinjection (i.e., intravenous injection) can be formulated using asterile solution or any pharmaceutically acceptable liquid as a vehicle.Pharmaceutically acceptable vehicles include, but are not limited to,sterile water, physiological saline, and cell culture media (e.g.,Dulbecco's Modified Eagle Medium (DMEM), α-Modified Eagles Medium(α-MEM), F-12 medium). Formulation methods are known in the art, seee.g., Banga (ed.) Therapeutic Peptides and Proteins: Formulation,Processing and Delivery Systems (2nd ed.) Taylor & Francis Group, CRCPress (2006).

The pharmaceutical composition may be formed in a unit dose form asneeded. The amount of active component, e.g., one or more anti-FcRnantibodies of the invention (e.g., N022-N024, N026, and N027, preferablyN027 and/or N024), included in the pharmaceutical preparations is suchthat a suitable dose within the designated range is provided (e.g., adose within the range of 0.01-500 mg/kg of body weight).

VI. Routes, Dosage, and Administration

Pharmaceutical compositions of the invention that contain one or moreanti-FcRn antibodies (e.g., N022-N024, N026, and N027, preferably N027and/or N024) as the therapeutic proteins may be formulated forintravenous administration, parenteral administration, subcutaneousadministration, intramuscular administration, intra-arterialadministration, intrathecal administration, or intraperitonealadministration. In particular, intravenous administration is preferred.The pharmaceutical composition may also be formulated for, oradministered via, oral, nasal, spray, aerosol, rectal, or vaginaladministration. For injectable formulations, various effectivepharmaceutical carriers are known in the art.

The dosage of the pharmaceutical compositions of the invention dependson factors including the route of administration, the disease to betreated, and physical characteristics, e.g., age, weight, generalhealth, of the subject. Typically, the amount of an anti-FcRn antibodyof the invention (e.g., any one of N022-N024, N026, and N027, preferablyN027 or N024) contained within a single dose may be an amount thateffectively prevents, delays, or treats the disease without inducingsignificant toxicity. A pharmaceutical composition of the invention mayinclude a dosage of an anti-FcRn antibody of the invention ranging from0.01 to 500 mg/kg (e.g., 0.01, 0.1, 0.2, 0.3, 0.4, 0.5, 1, 2, 3, 4, 5,10, 15, 20, 25, 30, 35, 40, 45, 50, 100, 150, 200, 250, 300, 350, 400,450, or 500 mg/kg) and, in a more specific embodiment, about 1 to about100 mg/kg and, in a more specific embodiment, about 1 to about 50 mg/kg.The dosage may be adapted by the physician in accordance withconventional factors such as the extent of the disease and differentparameters of the subject.

The pharmaceutical compositions are administered in a manner compatiblewith the dosage formulation and in such amount as is therapeuticallyeffective to result in an improvement or remediation of the symptoms.The pharmaceutical compositions are administered in a variety of dosageforms, e.g., intravenous dosage forms, subcutaneous dosage forms, andoral dosage forms (e.g., ingestible solutions, drug release capsules).Generally, therapeutic proteins are dosed at 1-100 mg/kg, e.g., 1-50mg/kg. Pharmaceutical compositions of the invention that contain ananti-FcRn antibody (e.g., any one of N022-N024, N026, and N027,preferably N027 or N024) may be administered to a subject in needthereof, for example, one or more times (e.g., 1-10 times or more)daily, weekly, monthly, biannually, annually, or as medically necessary.Dosages may be provided in either a single or multiple dosage regimens.The timing between administrations may decrease as the medical conditionimproves or increase as the health of the patient declines.

VII. Indications

The blockade of human FcRn by anti-FcRn antibodies of the invention maybe of therapeutic benefit in diseases that are driven by IgGautoantibodies. The ability of FcRn blockade to induce overall IgGcatabolism and removal of multiple species of autoantibodies withoutperturbing serum albumin, small circulating metabolites, or lipoproteinsoffers a method to expand the utility and accessibility of anautoantibody removal strategy to patients with autoantibody-drivenautoimmune disease pathology. While the invention is not bound bytheory, the dominant mechanism of action of an anti-FcRn antibody of theinvention may be to increase the catabolism of pathogenic autoantibodiesin circulation and decrease autoantibody and immune complex depositionin affected tissues.

The pharmaceutical compositions and methods of the invention containingone or more anti-FcRn antibodies (e.g., N022-N024, N026, and N027,preferably N027 and/or N024) are useful to promote catabolism andclearance of pathogenic antibodies, e.g., IgG and IgG autoantibodies ina subject, to reduce the immune response, e.g., to block immunecomplex-based activation of the immune response in a subject, and totreat immunological conditions or diseases in a subject. In particular,the pharmaceutical compositions and methods of the invention are usefulto reduce or treat an immune complex-based activation of an acute orchronic immune response. The acute immune response may be activated by amedical condition selected from the group consisting of pemphigusvulgaris, lupus nephritis, myasthenia gravis, Guillain-Barré syndrome,antibody-mediated rejection, catastrophic anti-phospholipid antibodysyndrome, immune complex-mediated vasculitis, glomerulitis, achannelopathy, neuromyelitis optica, autoimmune hearing loss, idiopathicthrombocytopenia purpura (ITP), autoimmune haemolytic anaemia (AIHA),immune neutropenia, dialated cardiomyopathy, and serum sickness. Thechronic immune response may be activated by a medical condition selectedfrom the group consisting of chronic inflammatory demyelinatingpolyneuropathy (CIDP), systemic lupus, a chronic form of a disorderindicated for acute treatment, reactive arthropathies, primary biliarycirrhosis, ulcerative colitis, and antineutrophil cytoplasmic antibody(ANCA)-associated vasculitis.

In some embodiments, the pharmaceutical compositions and methods of theinvention are useful to reduce or treat an immune response activated byan autoimmune disease. The autoimmune disease may be selected from thegroup consisting of alopecia areata, ankylosing spondylitis,antiphospholipid syndrome, Addison's disease, hemolytic anemia,autoimmune hepatitis, hepatitis. Behcets disease, bullous pemphigoid,cardiomyopathy, celiac sprue-dermatitis, chronic fatigue immunedysfunction syndrome, chronic inflammatory demyelinating polyneuropathy,Churg-Strauss syndrome, cicatricial pemphigoid, limited scleroderma(CREST syndrome), cold agglutinin disease, Crohn's disease,dermatomyositis, discoid lupus, essential mixed cryoglobulinemia,fibromyalgia, fibromyositis, Graves' disease, Hashimoto's thyroiditis,hypothyroidism, inflammatory bowel disease, autoimmunelymphoproliferative syndrome, idiopathic pulmonary fibrosis, IgAnephropathy, insulin dependent diabetes, juvenile arthritis, lichenplanus, lupus, Ménière's Disease, mixed connective tissue disease,multiple sclerosis, pernicious anemia, polyarteritis nodosa,polychondritis, polyglandular syndromes, polymyalgia rheumatica,polymyositis, primary agammaglobulinemia, primary biliary cirrhosis,psoriasis. Raynaud's phenomenon, Reiter's syndrome, rheumatic fever,rheumatoid arthritis, sarcoidosis, scleroderma, Sjögren's syndrome,stiff-man syndrome, Takayasu arteritis, temporal arteritis, ulcerativecolitis, uveitis, vitiligo, and Wegener's granulomatosis.

In particular, the pharmaceutical compositions and methods of theinvention are useful to reduce or treat an immune response activated bysystemic lupus erythematosus, antiphospholipid syndrome, pemphigusvulgaris/bullous pemphigoid, antineutrophil cytoplasmic antibody(ANCA)-associated vasculitis, myasthenia gravis, or neuromyelitisoptica.

EXAMPLES Example 1—Antibody Production

IgG heavy and light chain nucleic acid molecules were cloned in vectorpCDNA 3.3 using osteonectin secretion signals. HEK 293F cells were grownin Expi293 media at 37° C. with 8% CO₂. Cells were transfected at adensity of 3×10⁶/ml with 1 mg total DNA per liter. Enhancers were addedon days 2 and 3 following manufacturer's directions and the cells werecultured until day 5 or 6 before cell viability dropped to below 50% to60%. The cells were then spun out by centrifugation and the spent mediawas sterile filtered and stored at 4° C. until antibody purification.Antibodies were purified by a two-column procedure: POROS Protein Achromatography followed by POROS HS-50 cation exchange chromatography.The former separated most of the host cell proteins from the expressedantibodies while the latter removed the heavy chain dimers, light chaindimers, and half antibodies, as well as higher molecular weight species.The fractions from the HS-50 cation exchange column were pooled based onan SDS-PAGE gel analysis to maximize purity of the full lengthantibodies. The collected fractions were put over a Sephadex G50 bufferexchange column equilibrated in PBS at pH 7.2. The peak fractions werepooled and concentrated to greater than 10 mg/ml using 30 kDa spinconcentrators and frozen at −30° C. in 2 mg and 5 mg aliquots. The finalprotein samples were checked for purity by SDS-PAGE.

Example 2—Binding Affinities

Through affinity maturation, we identified more than 100 anti-FcRnantibodies having binding affinities to human FcRn with a K_(D) in thesub-micromolar range. Five antibodies (N022-N024, N026, and N027) wereselected for further characterization. Surface Plasmon Resonance (SPR)was used to determine the on- and off-rates (k_(a) and k_(d),respectively) for each of these five antibodies. Briefly, a Bio-Rad GLCsensor chip was inserted into the ProteOn XPR 36 and air initialized.After initialization the running buffer was switched to freshly preparedbuffer, either HBSP+ (0.01 M HEPES, 0.15 M NaCl, 0.05% P20. pH 7.4) orSodium Phosphate Buffer (0.02 M Sodium Phosphate, 0.15 M NaCl, 0.05%P20, pH 6.0) as appropriate, which was used for the remainder of theassay and for all dilutions. The chip was preconditioned using oneinjection each of 0.5% SDS, 50 mM NaOH and 10 mM HCl at 30 μl/min for 60seconds (s). A mouse anti-Human Fc mAb from GE Healthcare (BR100839) wasdiluted to 10 pg/ml in 10 mM acetate buffer pH 5.0 and approximately5,700 response units (RU) was immobilized using standard amine couplingchemistry in the horizontal orientation onto a GLC sensor chip. Theanti-hFcRn mAbs to be tested were captured onto the surface in thevertical orientation, with the goal of immobilizing approximately 200response units (RU) per interaction spot. The rhFcRn was diluted in afive-point three-fold dilution series starting at 1.25 μg/ml, leavingone lane as buffer-only for a double reference. The analyte was flowedacross the sensor surface in the horizontal orientation at 100 μl/minfor 240 s with a 3,600 s dissociation time. Regeneration wasaccomplished by injecting 3M MgCl₂ at 100 μl/min for 30 s in both thehorizontal and vertical directions. These procedures were repeated forall ligands.

Data analysis was conducted using the ProteOn Manager software. Eachinteraction step was adjusted for the Y and X direction using the AutoProcess tool, followed by interspot channel referencing to removenon-specific interactions and blank lane double referencing to removeassay drift. The data was fit using the Langmuir 1:1 kinetic model witha grouped Rmax. The k_(a), k_(d) and K_(D) values obtained from ProteOnManager in a single run were averaged and their percent CV wascalculated in Microsoft Excel when the N was three or greater.

Table 3 shows that five anti-FcRn antibodies of the invention, N022,N022, N024, N026, and N027, all bind with high affinity to human FcRn atpH 7.4. The equilibrium dissociation constant, K_(D), of the anti-FcRnantibodies of the invention ranged from 19.4 pM (N027) to 36.5 pM (N026)for binding to human FcRn at pH 7.4. Table 3 also shows the rapidon-rates and slow off-rates of the five anti-FcRn antibodies. At pH 7.4,the on-rates were in the range of 0.93-1.42×10⁶ 1/Ms for binding tohuman FcRn. The off-rates were in the range of 2.31-4.44×10⁶ 1/s.

TABLE 3 k_(a) (1/Ms) k_(d) (1/s) K_(D) (M) R_(max) Chi2 K_(D) (pM) N0221.42E+06 4.42E−05 3.10E−11 146.93 7.65 31 N023 9.27E+05 2.91E−053.14E−11 193.43 5.26 31.4 N024 1.13E+06 4.03E−05 3.55E−11 181.17 6.1235.5 N026 1.22E+06 4.44E−05 3.65E−11 163.9 5.68 36.5 N027 1.19E+062.31E−05 1.94E−11 211.33 7.81 19.4

Example 3—IgG Competition

The ability of anti-FcRn antibodies of the invention to compete with IgGfor binding to human or cynomolgus monkey FcRn was evaluated on humanembryonic kidney (HEK) 293 cells ectopically expressing cell surface,glycophosphatidylinositol (GPI)-linked FcRn. Human and cynomolgus monkeyFcRn alpha amino acid sequences exhibit 97.5% sequence identity. Nineamino acid residues of 355 are different between human and cynomolgusmonkey FcRn alpha, but none are in the epitope-mapped binding region.The level of cell-bound IgG was determined using 66 nM of fluorescentprobe-labeled, non-specific IgG. The binding of IgG to cell surface FcRnwas done at pH 6.0, which allows the Fc portion of IgG to interact withFcRn. As shown in FIG. 1, the amount of cell-bound IgG significantlydecreased as the concentration of the anti-FcRn antibody (N022-N024,N026, or N027) increased. The binding of IgG was inhibited in aconcentration- and saturation-dependent manner by each of the fiveexemplary anti-FcRn antibodies of the invention, demonstrating theability of the anti-FcRn antibodies, N022-N024, N026, and N027, toeffectively compete with and inhibit binding of IgG to FcRn at pH 6.0.The EC50 values of the antibodies ranged between 2 and 6 nM.

Example 4—Effect of Anti-FcRn Antibodies on IgG Catabolism in Mice

To measure the effect of the anti-FcRn antibodies of the invention onIgG catabolism in vivo, human FcRn transgenic mouse strain FcRn−/−hFcRn(32) Tg mice, which lacks mouse FcRn but expresses human FcRn in atissue distribution similar to the endogenous mouse and human FcRn, wasused. FcRn−/−hFcRn (32) Tg mice injected with 500 mg/kg human IgG on day0 were administered a single dose of an anti-FcRn antibody at 10 mg/kgon days 1 and 4. As shown in FIG. 2, the catabolism of IgG was increasedby the administration of anti-FcRn antibodies as seen by lower levels ofIgG measured over time in anti-FcRn antibody-treated mice. Theactivities of N024 (K_(D)=35.5 pM), N026 (K_(D)=36.5 pM), and N027(K_(D)=19.4 pM) appeared to be to be similar at 10 mg/kg.

Example 5—In Vitro and In Vivo Functional Characterizations of Anti-FcRnAntibodies

In Vitro

Cellular binding affinities of the antibodies of the invention weremeasured on human embryonic kidney (HEK) 293 cells ectopicallyexpressing cell surface, glycophosphatidylinositol (GPI)-linked human orcynomolgus monkey FcRn. FcRn is a type I transmembrane protein with theIgG and albumin binding domains oriented to the luminal side ofendosomal membranes or to the cell surface when transported to theplasma membrane. The binding of anti-FcRn antibodies to cell surface,membrane-associated FcRn on HEK293 cells at pH 7.4 mimics binding in aphysiologically-relevant environment and at the pH where only the Fabdomain and not the Fc domain of the antibodies interact with FcRn. TheFcRn extracellular domain was displayed on the cell surface at highdensity through a C-terminal engineered GPI linkage. The anti-FcRnantibodies of the invention were labeled with a fluorescent probe. Theantibodies were allowed to bind for 30 minutes on ice. Cells were thenwashed at 4° C. and bound antibodies were detected using afluorophore-labeled secondary antibody, e.g., a goat anti-human IgGF(ab)₂. The binding to human FcRn was concentration dependent andantibodies of the invention displayed EC50 values ranging from 4 to 7nM.

Cellular binding affinities of the antibodies of the invention were alsomeasured on endogenously expressed human FcRn. Monocytes express thehighest levels of FcRn and show the highest percent positivity for FcRnexpression in mouse and human blood. Monocytic cell line THP-1 was usedto evaluate binding of anti-FcRn antibodies to endogenous human FcRn atpH 7.4. Since endogenous FcRn is primarily in intracellular endosomalvesicles in THP-1 cells, the cells were first permeablized with a milddetergent and fixed prior to incubation for 30 minutes at 4° C. withanti-FcRn antibodies in the presence of bovine serum to blocknon-specific Fc receptor binding. This assay was able to distinguishantibodies with better binding to endogenous human FcRn. The binding ofanti-FcRn antibodies to THP-1 cells is concentration dependent. Allantibodies of the invention, e.g., N022-N024, N026, and N027, showedbetter binding affinities than IgG1. Antibody N027 displayed the highestbinding affinity with an EC50 value of 3.0 nM.

The ability of anti-FcRn antibodies of the invention to compete with IgGfor binding to human or cynomolgus monkey FcRn was evaluated on humanembryonic kidney (HEK) 293 cells ectopically expressing cell surface,GPI-linked FcRn. The level of cell-bound IgG was determined usingfluorescent probe-labeled, non-specific IgG. The binding of IgG to cellsurface FcRn was done at pH 6.0, which allows the Fc portion of IgG tointeract with FcRn. As shown in Example 3 and FIG. 1, the amount ofcell-bound IgG significantly decreased as the concentration of theanti-FcRn antibody increased. The binding of IgG was inhibited in aconcentration- and saturation-dependent manner by each of the fiveexemplary anti-FcRn antibodies of the invention, e.g., N022-N024, N026,and N027, demonstrating the ability of the anti-FcRn antibodies toeffectively compete with and inhibit binding of IgG to FcRn at pH 6.0.The EC50 values of the antibodies ranged from 2 to 6 nM.

Epitope mapping by hydrogen-deuterium exchange of the antibodies of theinvention indicated that the antibodies bind to an epitope on human FcRnlocated in and/or adjacent to the Fc-FcRn interaction interface, whichsuggests that the antibodies of the invention block IgG binding to FcRnby direction inhibition. Furthermore, the epitope-mapped binding site isdistant from the albumin-binding site of FcRn, thus, serumalbumin-binding should not be inhibited and serum albumin levels shouldnot be decreased. An enzyme-linked immunosorbent assay (ELISA) was usedto confirm that the antibodies of the invention do not inhibit serumalbumin binding to FcRn. Soluble His-tagged extracellular domain ofhuman FcRn was bound to the plate surface and pre-incubated withincreasing concentrations of anti-FcRn antibody at pH 6.0. Horseradishperoxidase (HRP)-conjugated human serum albumin was allowed to bind tothe soluble, His-tagged FcRn. None of the antibodies inhibited albuminbinding to FcRn. Furthermore, in vivo experimental evidence also showedthat mouse albumin levels remained constant after anti-FcRn antibodyadministration, indicating that albumin recycling was not disturbed byantibody binding to FcRn.

In Vivo

To test the in vivo effect of anti-FcRn antibodies of the invention onIgG catabolism, human FcRn transgenic mouse strain FcRn−/−hFcRn (32) Tgmice, which lack mouse FcRn but express human FcRn in a tissuedistribution similar to that of the endogenous mouse and human FcRn,were used. FcRn−/−hFcRn (32) Tg mice injected with human IgG on day 0were administered a single dose of an anti-FcRn antibody at 10 mg/kg ondays 1 and 4. As shown in Example 3 and FIG. 2, the catabolism of IgGwas increased by the administration of anti-FcRn antibodies as seen bylower levels of IgG measured over time in anti-FcRn antibody-treatedmice. The activities of N024 (K_(D)=35.5 pM), N026 (K_(D)=36.5 pM), andN027 (K_(D)=19.4 pM) appeared to be to be similar at 10 mg/kg.

Example 6—Effect of Anti-FcRn Antibodies on IgG Levels and TargetOccupancy in Mice

N027 was dosed intravenously (i.v.) 24 hrs after administration of 500mg/kg IVIg (tracer) to Tg32 human FcRn (hFCGRT) transgenic, mouse FcRn(mFCGRT) knockout mice. Circulating human IgG was detected by ELISA oneach day. Target occupancy was measured on each day in monocytes fromlysed whole blood by fluorescence-activated cell sorting (FACS), afterincubation of cells with immunophenotyping cell surface markers followedby fixation and permeabilization. Unoccupied FcRn was measured bystaining with Dy650-labeled N027 (n=4 males per group). As shown in FIG.3, IgG level and the percentage of unoccupied FcRn were decreased by theadministration of N027 in a dose-dependent manner.

Example 7—Selective Induction of IgG Catabolism and Target Occupancy inCynomolgus Monkeys

N027 was dosed i.v. at t=0 in cynomolgus monkeys. Circulating endogenousIgG and albumin was detected by ELISA. Target occupancy was measured inmonocytes from lysed whole blood by FACS, after incubation of cells withimmunophenotyping cell surface markers followed by fixation andpermeabilization. Unoccupied FcRn was measured by staining withDy650-labeled N027. (n=3 males per group). As shown in FIG. 4, IgG leveland the percentage of unoccupied FcRn were decreased by theadministration of N027 in a dose-dependent manner, while plasma albuminlevel stayed unchanged.

Example 8—Biodistribution of N027 in Mice

N027 or isotype human IgG1 control antibody labeled with fluorophore(VT680) was administered i.v. to Tg32 human FcRn transgenic, mouse FcRnknockout mice at 30 mg/kg. Levels of labeled antibody were measured inindividual organs by quantitative ex vivo optical imaging. FIG. 5 showsthe biodistribution of N027 in various organs in mice.

Example 9—Efficacy of N027 in Mouse Collagen Antibody-Induced Arthritis

Collagen antibody-induced arthritis was induced in Tg32 human FcRntransgenic, mouse FcRn knockout mice by intraperitoneal (i.p.) injectionof ArthritoMab™ cocktail (MD Biosciences) on day 1 and inflammatorydisease activity induced with 100 μg LPS i.p. on day 4. N027 was dosedtherapeutically i.v. at 5 mg/kg (arrow), on day 6 post disease inductionand randomization. IVIG at 1 g/kg (positive control group) orvehicle-PBS (negative control) were dosed on day 6 after randomization(n=5 per group). As shown in FIG. 6, N027 potently inhibits collagenantibody-induced arthritis in human transgenic FcRn mice when dosedtherapeutically.

Example 10—Efficacy of N027 in Mouse Chronic Idiopathic ThrombocytopeniaPurpura (ITP)

Thrombocytopenia was induced in Tg32 human FcRn (hFCGRT) transgenic,mouse FcRn (mFCGRT) knockout mice by continuous infusion ofanti-platelet antibody (anti-CD41, MWReg30) subcutaneous (s.c.)miniosmotic pump. Circulating platelet levels were decreased to300×109/L or less by 72 hrs (Day 3) after pump implantation. N027 wasdosed therapeutically i.v. 72 hrs (day 3) and 120 hrs (Day 5) post-pumpimplantation (A, n=4 per group; B, n=7 per group). FIG. 7 shows theeffects of N027 on platelet levels in mice having thrombocytopenia.

Other Embodiments

While the invention has been described in connection with specificembodiments thereof, it will be understood that it is capable of furthermodifications and this application is intended to cover any variations,uses, or adaptations of the invention following, in general, theprinciples of the invention and including such departures from thepresent disclosure come within known or customary practice within theart to which the invention pertains and may be applied to the essentialfeatures hereinbefore set forth.

All publications, patents, and patent applications are hereinincorporated by reference in their entirety to the same extent as ifeach individual publication, patent or patent application wasspecifically and individually indicated to be incorporated by referencein its entirety.

Other embodiments are within the following claims.

What is claimed is:
 1. (canceled)
 2. A method for treating a disorderselected from the group consisting of pemphigus vulgaris, lupusnephritis, myasthenia gravis, Guillain-Barré syndrome, antibody-mediatedrejection, catastrophic anti-phospholipid antibody syndrome, immunecomplex-mediated vasculitis, glomerulitis, a channelopathy,neuromyelitis optica, autoimmune hearing loss, idiopathicthrombocytopenia purpura (ITP), autoimmune haemolytic anaemia (AIHA),immune neutropenia, dilated cardiomyopathy, and serum sickness,comprising administering to a patient in need thereof, an antibody thatbinds to human FcRn, the antibody comprising: (1) a light chain variableregion comprising a CDR L1, a CDR L2, and a CDR L3 and (2) a heavy chainvariable region comprising a CDR H1, a CDR H2, and a CDR H3, wherein theisolated antibody is selected from the group consisting of: (a) anantibody wherein CDR L1 comprises the amino acid sequence TGTGSDVGSYNLVS(SEQ ID NO: 1), CDR L2 comprises the amino acid sequence GDSERPS (SEQ IDNO: 2), CDR L3 comprises the amino acid sequence SSYAGSGIYV (SEQ ID NO:3), CDR H1 comprises the amino acid sequence TYAMG (SEQ ID NO: 4), CDRH2 comprise the amino acid sequence SIGSSGAQTRYADS (SEQ ID NO: 7), andCDR H3 comprises the amino acid sequence LAIGDSY (SEQ ID NO: 11); (b) anantibody wherein CDR L1 comprises the amino acid sequence TGTGSDVGSYNLVS(SEQ ID NO: 1), CDR L2 comprises the amino acid sequence GDSERPS (SEQ IDNO: 2), CDR L3 comprises the amino acid sequence SSYAGSGIYV (SEQ ID NO:3), CDR H1 comprises the amino acid sequence DYAMG (SEQ ID NO: 5), CDRH2 comprise the amino acid sequence SIGASGSQTRYADS (SEQ ID NO: 8), andCDR H3 comprises the amino acid sequence LAIGDSY (SEQ ID NO: 11); (c) anantibody wherein CDR L1 comprises the amino acid sequence TGTGSDVGSYNLVS(SEQ ID NO: 1), CDR L2 comprises the amino acid sequence GDSERPS (SEQ IDNO: 2), CDR L3 comprises the amino acid sequence SSYAGSGIYV (SEQ ID NO:3), CDR H1 comprises the amino acid sequence NYAMG (SEQ ID NO: 6), CDRH2 comprise the amino acid sequence SIGASGAQTRYADS (SEQ ID NO: 9), andCDR H3 comprises the amino acid sequence LAIGDSY (SEQ ID NO: 11); (d) anantibody wherein CDR L1 comprises the amino acid sequence TGTGSDVGSYNLVS(SEQ ID NO: 1), CDR L2 comprises the amino acid sequence GDSERPS (SEQ IDNO: 2), CDR L3 comprises the amino acid sequence SSYAGSGIYV (SEQ ID NO:3), CDR H1 comprises the amino acid sequence TYAMG (SEQ ID NO: 4), CDRH2 comprise the amino acid sequence SIGASGGQTRYADS (SEQ ID NO: 10), andCDR H3 comprises the amino acid sequence LAIGDSY (SEQ ID NO: 11); and(e) an antibody wherein CDR L1 comprises the amino acid sequenceTGTGSDVGSYNLVS (SEQ ID NO: 1), CDR L2 comprises the amino acid sequenceGDSERPS (SEQ ID NO: 2), CDR L3 comprises the amino acid sequenceSSYAGSGIYV (SEQ ID NO: 3), CDR H1 comprises the amino acid sequenceTYAMG (SEQ ID NO: 4), CDR H2 comprise the amino acid sequenceSIGASGSQTRYADS (SEQ ID NO: 8) and CDR H3 comprises the amino acidsequence LAIGDSY (SEQ ID NO: 11).
 3. The method of claim 2, wherein CDRL1 comprises the amino acid sequence TGTGSDVGSYNLVS (SEQ ID NO: 1), CDRL2 comprises the amino acid sequence GDSERPS (SEQ ID NO: 2), CDR L3comprises the amino acid sequence SSYAGSGIYV (SEQ ID NO: 3), CDR H1comprises the amino acid sequence TYAMG (SEQ ID NO: 4), CDR H2 comprisesthe amino acid sequence SIGASGSQTRYADS (SEQ ID NO: 8), and CDR H3comprises the amino acid sequence LAIGDSY (SEQ ID NO: 11).
 4. The methodof claim 2, wherein CDR L1 comprises the amino acid sequenceTGTGSDVGSYNLVS (SEQ ID NO: 1), CDR L2 comprises the amino acid sequenceGDSERPS (SEQ ID NO: 2), CDR L3 comprises the amino acid sequenceSSYAGSGIYV (SEQ ID NO: 3), CDR H1 comprises the amino acid sequenceTYAMG (SEQ ID NO: 4), CDR H2 comprise the amino acid sequenceSIGSSGAQTRYADS (SEQ ID NO: 7), and CDR H3 comprises the amino acidsequence LAIGDSY (SEQ ID NO: 11); and the light chain of comprises anamino acid sequence having at least 90% identity to (SEQ ID NO: 19)QSALTQPASVSGSPGQSITISCTGTGSDVGSYNLVSWYQQHPGKAPKLMIYGDSERPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYAGSGIYVFGTGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHKSYS CQVTHEGSTVEKTVAPTECS.


5. The method of claim 2, wherein CDR L1 comprises the amino acidsequence TGTGSDVGSYNLVS (SEQ ID NO: 1), CDR L2 comprises the amino acidsequence GDSERPS (SEQ ID NO: 2), CDR L3 comprises the amino acidsequences SSYAGSGIYV (SEQ ID NO: 3), CDR H1 comprises the amino acidsequence TYAMG (SEQ ID NO: 4), CDR H2 comprise the amino acid sequenceSIGASGSQTRYADS (SEQ ID NO: 8), and CDR H3 comprises the amino acidsequence LAIGDSY (SEQ ID NO: 11); and the heavy chain comprises an aminoacid sequence having at least 90% identity to (SEQ ID NO: 24)EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMGWVRQAPGKGLEWVSSIGASGSQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS LSPG.


6. The method of claim 2, wherein the antibody is selected from thegroup consisting of: (a) an antibody comprising a light chain comprisingthe amino acid sequence (SEQ ID NO: 19)QSALTQPASVSGSPGQSITISCTGTGSDVGSYNLVSWYQQHPGKAPKLMIYGDSERPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYAGSGIYVFGTGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHKSYS CQVTHEGSTVEKTVAPTECS;

and a heavy chain comprising the amino acid sequence (SEQ ID NO: 24)EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMGWVRQAPGKGLEWVSSIGASGSQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS LSPG;

(b) an antibody comprising a light chain comprising the amino acidsequence (SEQ ID NO: 19)QSALTQPASVSGSPGQSITISCTGTGSDVGSYNLVSWYQQHPGKAPKLMIYGDSERPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYAGSGIYVFGTGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHKSYS CQVTHEGSTVEKTVAPTECS;

and a heavy chain comprising the amino acid sequence (SEQ ID NO: 20)EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMGWVRQAPGKGLEWVSSIGSSGAQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLS PG;

(c) an antibody comprising a light chain comprising the amino acidsequence (SEQ ID NO: 19)QSALTQPASVSGSPGQSITISCTGTGSDVGSYNLVSWYQQHPGKAPKLMIYGDSERPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYAGSGIYVFGTGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHKSYS CQVTHEGSTVEKTVAPTECS;

and a heavy chain comprising the amino acid sequence (SEQ ID NO: 21)EVQLLESGGGLVQPGGSLRLSCAASGFTFSDYAMGWVRQAPGKGLEWVSSIGASGSQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL SPG;

(d) an antibody comprising a light chain comprising the amino acidsequence (SEQ ID NO: 19)QSALTQPASVSGSPGQSITISCTGTGSDVGSYNLVSWYQQHPGKAPKLMIYGDSERPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYAGSGIYVFGTGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHKSYS CQVTHEGSTVEKTVAPTECS;

and a heavy chain comprising the amino acid sequence (SEQ ID NO: 22)EVQLLESGGGLVQPGGSLRLSCAASGFTFSNYAMGWVRQAPGKGLEWVSSIGASGAQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL SPG;

and (e) an antibody comprising a light chain comprising the amino acidsequence (SEQ ID NO: 19)QSALTQPASVSGSPGQSITISCTGTGSDVGSYNLVSWYQQHPGKAPKLMIYGDSERPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYAGSGIYVFGTGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHKSYS CQVTHEGSTVEKTVAPTECS;

and a heavy chain comprising the amino acid sequence (SEQ ID NO: 23)EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMGWVRQAPGKGLEWVSSIGASGGQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL SPG.


7. The method of claim 2, wherein the antibody comprises an IgG1 heavychain having an amino acid substitution N297A, numbered according to theEU numbering system.
 8. The method of claim 2, wherein the antibodycomprises a light chain comprising CDR L1, CDR L2 and CDR L3 and a heavychain comprising CDR H1, CDR H2 and CDR H3, wherein CDR L1 comprises theamino acid sequence TGTGSDVGSYNLVS (SEQ ID NO: 1), CDR L2 comprises theamino acid sequence GDSERPS (SEQ ID NO: 2), CDR L3 comprises the aminoacid sequences SSYAGSGIYV (SEQ ID NO: 3), CDR H1 comprises the aminoacid sequence TYAMG (SEQ ID NO: 4), CDR H2 comprise the amino acidsequence SIGSSGAQTRYADS (SEQ ID NO: 7), and CDR H3 comprises the aminoacid sequence LAIGDSY (SEQ ID NO: 11); and the heavy chain comprises anamino acid sequence having at least 90% identity to (SEQ ID NO: 20)EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMGWVRQAPGKGLEWVSSIGSSGAQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL SPG.


9. The method of claim 2, wherein the antibody comprises a light chaincomprising CDR L1, CDR L2 and CDR L3 and a heavy chain comprising CDRH1, CDR H2 and CDR H3, wherein CDR L1 comprises the amino acid sequenceTGTGSDVGSYNLVS (SEQ ID NO: 1), CDR L2 comprises the amino acid sequenceGDSERPS (SEQ ID NO: 2), CDR L3 comprises the amino acid sequencesSSYAGSGIYV (SEQ ID NO: 3), CDR H1 comprises the amino acid sequenceDYAMG (SEQ ID NO: 5), CDR H2 comprise the amino acid sequenceSIGASGSQTRYADS (SEQ ID NO: 8), and CDR H3 comprises the amino acidsequence LAIGDSY (SEQ ID NO: 11); and the heavy chain comprises an aminoacid sequence having at least 90% identity to (SEQ ID NO: 21)EVQLLESGGGLVQPGGSLRLSCAASGFTFSDYAMGWVRQAPGKGLEWVSSIGASGSQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL SPG.


10. The method of claim 2, wherein the antibody comprises a light chaincomprising CDR L1, CDR L2 and CDR L3 and a heavy chain comprising CDRH1, CDR H2 and CDR H3, wherein CDR L1 comprises the amino acid sequenceTGTGSDVGSYNLVS (SEQ ID NO: 1), CDR L2 comprises the amino acid sequenceGDSERPS (SEQ ID NO: 2), CDR L3 comprises the amino acid sequencesSSYAGSGIYV (SEQ ID NO: 3), CDR H1 comprises the amino acid sequenceNYAMG (SEQ ID NO: 6), CDR H2 comprise the amino acid sequenceSIGASGAQTRYADS (SEQ ID NO: 9), and CDR H3 comprises the amino acidsequence LAIGDSY (SEQ ID NO: 11); and the heavy chain comprises an aminoacid sequence having at least 90% identity to (SEQ ID NO: 22)EVQLLESGGGLVQPGGSLRLSCAASGFTFSNYAMGWVRQAPGKGLEWVSSIGASGAQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL SPG.


11. The method of claim 2, wherein the antibody comprises a a lightchain comprising CDR L1, CDR L2 and CDR L3 and a heavy chain comprisingCDR H1, CDR H2 and CDR H3, wherein CDR L1 comprises the amino acidsequence TGTGSDVGSYNLVS (SEQ ID NO: 1), CDR L2 comprises the amino acidsequence GDSERPS (SEQ ID NO: 2), CDR L3 comprises the amino acidsequences SSYAGSGIYV (SEQ ID NO: 3), CDR H1 comprises the amino acidsequence TYAMG (SEQ ID NO: 4), CDR H2 comprise the amino acid sequenceSIGASGGQTRYADS (SEQ ID NO: 10), and CDR H3 comprises the amino acidsequence LAIGDSY (SEQ ID NO: 11); and the heavy chain comprises an aminoacid sequence having at least 90% identity to (SEQ ID NO: 23)EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMGWVRQAPGKGLEWVSSIGASGGQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL SPG.


12. The method of claim 8, wherein the heavy chain comprises an aminoacid sequence having at least 95% identity to (SEQ ID NO: 20)EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMGWVRQAPGKGLEWVSSIGSSGAQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG.


13. The method of claim 9, wherein the heavy chain comprises an aminoacid sequence having at least 95% identity to (SEQ ID NO: 21)EVQLLESGGGLVQPGGSLRLSCAASGFTFSDYAMGWVRQAPGKGLEWVSSIGASGSQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG.


14. The method of claim 10, wherein the heavy chain comprises an aminoacid sequence having at least 95% identity to (SEQ ID NO: 22)EVQLLESGGGLVQPGGSLRLSCAASGFTFSNYAMGWVRQAPGKGLEWVSSIGASGAQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG.


15. The method of claim 10, wherein the heavy chain comprises an aminoacid sequence having at least 95% identity to (SEQ ID NO: 23)EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMGWVRQAPGKGLEWVSSIGASGGQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG.


16. The method of claim 5, wherein the heavy chain comprises an aminoacid sequence having at least 95% identity to (SEQ ID NO: 24)EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMGWVRQAPGKGLEWVSSIGASGSQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG.


17. The method of claim 2, wherein the antibody is an IgG antibodylacking effector function.
 18. The method of claim 2, wherein theantibody lacks effector function.
 19. The method of claim 2, wherein thedisorder is myasthenia gravis.
 20. The method of claim 2, the disorderis autoimmune haemolytic anaemia.